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1
Hewitt, Susannah Louise. "T helper 1/T helper 2 commitment and nuclear localisation." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415427.
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Passini, Nadia. "Molecular mechanisms of T helper 1 and T helper 2 cell development : differential signaling in response to Interleukin-12." Thesis, Open University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299005.
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Kelly, Helena T. "The role of T helper 1 and T helper 2 lymphocyte subsets in the pathogenesis of experimental autoimmune uveoretinitis." Thesis, University of Aberdeen, 1995. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU543992.
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CD4+ T cells can be subdivided on the basis of their lymphokine repertoire produced on activation resulting in TH1 like and TH2 like populations. The purpose of this study was to measure the intraocular expression of cytokines as a means of defining the CD4+ lymphocyte subsets present during the development of uveoretinitis. Lewis rats were immunised with retinal antigen and pertussis toxin resulting in early signs of disease activity evident by day 9 with increasing severity evident by day 12. Extensive clinical and histological damage was observed by day 14 with a reduction in severity through to end stage disease at day 24. In this study, the failure to establish pure populations of retinal antigen specific T lymphocyte cell lines and the observation of the lack of sensitivity of Northern hybridization to signals expressed at low levels resulted in the more sensitive technique of RT-PCR being utilized. Both IL2 and IFN mRNA expression was detected at all stages of disease with highest levels being present early in uveitis. In contrast IL4 mRNA levels increased with disease progression. This study suggests a pathogenic role for TH1 like cells and a protective role for TH2 like cells in this autoimmune disease. In order to provide an insight into alternative treatment strategies of the disease, immunomodulation of EAU was carried out using the immunosuppressive drugs CsA, FK506 and rapamycin and the resultant cytokine mRNA profiles examined. The results indicated that CsA and FK506 downregulated the TH1 response having suppressive effects on the levels of IL2 and IFN mRNA respectively. In contrast rapamycin was found to modulate the TH2 response enhancing IL4 levels. From this data, a drug based strategy employing rapamycin appears to be the most favourable approach.
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Kropf, Pascale. "Characterisation of T Helper 2 responses in non-healing Leishmania major infections." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395473.
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Özgönen, Özlem Şahin Ünal. "Malign ve tüberküloz plörezi ayırıcı tanısında T helper 1 ve T helper 2 sitokinlerden IFN-y,IL-12,IL-18 ve IL-10'un tanısal değeri /." Isparta: SDÜ Tıp Fakültesi, 2006. http://tez.sdu.edu.tr/Tezler/TT00277.pdf.
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MacKenzie, Jason Roderick, and Jason Mackenzie@ipaustralia gov au. "The Role of Eosinophils in the Regulation of CD4+ T helper 2 Regulated Inflammation." The Australian National University. The John Curtin School of Medical Research, 2004. http://thesis.anu.edu.au./public/adt-ANU20051007.121844.
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The eosinophil is a leukocyte whose intracellular mediators are considered to play a
central role in the pathogenesis of allergic diseases, including allergic asthma, allergic
rhinitis and atopic dermatitis, and which is also involved in immunological responses to
parasites. Eosinophil differentiation and maturation from bone marrow progenitors is
regulated by interleukin-5 (IL-5), which may be secreted by T helper 2 (Th2) T
lymphocytes, and is consistently upregulated in allergic conditions. Eotaxin is a potent
chemoattractant for circulating and tissue eosinophils, and the production of this
chemokine promotes eosinophil infiltration and accumulation within sites of allergic
inflammation.¶
Eosinophils obtained from inflammatory tissues and secretions display an altered
phenotype in comparison to peripheral blood eosinophils, with increased surface
expression of major histocompatibility complex (MHC) proteins and adhesion
molecules (Hansel et al., 1991), and migration across the microvascular endothelium
may also increase their capacity to generate an oxidative burst (Walker et al., 1993;
Yamamoto et al., 2000). Eosinophils are phagocytic cells, and have been shown to
present simple (no requirement for intracellular processing) and complex antigens to
MHC-restricted, antigen-specific T lymphocytes (Del Pozo et al., 1992; Weller et al.,
1993). Furthermore, eosinophils express the costimulatory molecules required for
effective antigen presentation (Tamura et al., 1996), and ligation of costimulatory
molecules on the eosinophil cell surface can induce the release of eosinophil derived
cytokines (Woerly et al., 1999; Woerly et al., 2002). Therefore the eosinophil may also
regulate immune responses.¶
To date, no studies have demonstrated the ability of eosinophils to modulate activated T
lymphocyte function via presentation of relevant antigen in the context of MHC class II
(MHC-II), concomitant with Th2 cytokine release. In the experiments described in this
thesis, murine eosinophils have been observed to rapidly migrate to sites of antigen
deposition within the airways mucosa of naïve mice, suggesting a potential role for this
granulocyte in the primary response to inhaled antigen. However, human allergic
diseases are often diagnosed after the establishment of allergic responses, and symptom
development. Therefore, a murine model of allergic airways disease (AAD) was used to
investigate the ability for eosinophils to participate as antigen presenting cells (APCs),
and thereby modulate activated T lymphocyte function both in vitro and in vivo.
Detailed histological analysis of the pulmonary draining lymph nodes following antigen
challenge in sensitised mice revealed a rapid infiltration of eosinophils into this tissue,
which preceded the accumulation of eosinophils in bronchoalveolar lavage fluid
(BALF). This suggested that eosinophils were preferentially translocating to the
draining lymph nodes following antigen challenge, and that the subsequent
accumulation of these cells in the BALF was a consequence of continued antigen
delivery to the lower airways.¶
Eosinophil trafficking to lymphoid tissue via the afferent lymphatics was substantiated
using electron microscopy of lymph node sections and the intravenous (i.v.) transfer of
fluorescently labeled eosinophils, which did not traffic to lymph nodes via the blood.
During the resolution of AAD, eosinophils were noted for their persistence in the
pulmonary draining lymph nodes. These observations suggested a continued modulation
of T cell function by lymph node dwelling eosinophils during AAD resolution,
particularly in light of recent observations for draining lymph node T cell proliferation
following instillation of antigen-pulsed eosinophils into the allergic mouse lung (Shi et
al., 2000).¶
To further investigate the antigen presenting capacity, eosinophils were obtained from
the BALF of mice with AAD, and their surface expression of MHC class II (MHC-II)
proteins and costimulatory molecules confirmed using flow cytometric analysis. The
ability to acquire and process complex antigen both in vitro and in vivo was also
confirmed using naturally quenching fluorescenated ovalbumin (OVA), which is
degraded into fluorescent peptides by the action of intracellular proteases. Thus,
eosinophil expression of the surface molecules necessary for effective antigen
presentation was confirmed, as was their ability to process complex antigen. Further
investigations revealed that eosinophils can present complex OVA antigen to CD4+ T
lymphocytes obtained from the allergic mouse, and to in vitro derived OVA-specific
Th2 cells. In the presence of exogenous antigen, eosinophils co-cultured with T
lymphocytes were able to induce Th2 cytokine production, and demonstrated an ability
for eosinophils to modulate T lymphocyte function in vitro.¶
The ability for eosinophils to act as antigen presenting cells in vivo was also
investigated. Eosinophils obtained from the antigen-saturated lungs of OVA sensitised
and challenged mice were transferred to the peritoneal cavities of naïve host mice.
When subsequently challenged with aerosolised OVA, eosinophil recipients developed
a pulmonary eosinophilia similar to that of OVA sensitised and challenged mice. To
validate this finding, the experimental procedure was altered to accommodate the use of
non-allergy derived eosinophils, which were pulsed with OVA in vitro, prior to transfer
into naïve recipients. When subsequently challenged with aerosolised OVA, eosinophil
recipients developed a peripheral blood and pulmonary eosinophilia, and stimulation
with OVA induced IL-5 and IL-13 cytokine production from pulmonary draining lymph
node cells. Notably, the AAD induced by transfer of antigen pulsed eosinophils did not
induce detectable OVA-specific IgG1, which may be attributed to the lack of soluble
antigen required for B cell antibody production.¶
During the course of these investigations, an OVA T cell receptor (TCR) transgenic
mouse (OT-II) was procured with a view to defining the interaction between eosinophils
and activated T lymphocytes (Barnden et al., 1998). Despite having specificity for the
OVA323-339 peptide, an immunodominant epitope that skews naïve T cell responses
towards Th2 cytokine release (Janssen et al., 2000), T lymphocytes from the OT-II
mouse preferentially secreted IFN-γ in response to stimulation with either OVA peptide
or OVA. These mice were further characterised in a mouse model of AAD, and found to
be refractory to disease induction and progression, which may be attributed to
significant IFN-γ secretion by transgenic CD4+ T lymphocytes during antigen
sensitisation. Indeed, these cells were noted for their ability to attenuate pulmonary
eosinophilia when transferred to OVA sensitised and challenged wild type mice,
although serum OVA-specific IgG1, peripheral blood eosinophilia levels and airways
response to methacholine challenge remained intact.¶
Knowledge of the biased Th1 phenotype in naïve OT-II provided a unique opportunity
to investigate the fate of T lymphocytes bearing high affinity OVA-specific TCRs
following neonatal antigen exposure to soluble OVA. In a previous study, subcutaneous
(s.c.) administration of soluble OVA to wild type neonatal mice was suspected to have
deleted OVA-specific T cells from the T cell repertoire (Hogan et al., 1998a). Using
flow cytometry and TCR specific antibody, the delivery of s.c. OVA to OT-II neonates did not alter transgenic T cell populations in adult mice. Instead, it was surprising to
find a skewing towards the Th2 phenotype and loss of IFN-γ secretion following OVA
sensitisation and challenge in adult mice. A mechanism for this reprogramming of the
transgenic T cell from the Th1 to a Th2 phenotype following OT-II neonatal exposure
to soluble OVA is proposed, and further experimentation may validate this hypothesis.¶
In conclusion, eosinophils residing in the allergic lung have the capacity to interact with
activated T cells, both within this tissue and the draining lymph nodes. Despite their
relative inefficiency as antigen presenting cells (Mawhorter et al., 1994), eosinophils
may participate en masse in the serial triggering of activated TCRs, and provide
appropriate costimulatory signals that modulate T lymphocyte function. Through the
elaboration of Th2 cytokines and stimulation of T cell proliferation, antigen presenting
eosinophils may transiently prolong or exacerbate the symptoms of allergic diseases.
Alternatively, eosinophils presenting relevant antigens may inhibit T cell activity via
degranulation, and such activity has recently been observed in a parasite model (Shinkai
et al., 2002). Finally, experiments in the OT-II mouse have provided valuable
information to suggest that therapies designed to modulate eosinophil numbers in
allergic tissues through the secretion of opposing cytokines such as IFN-γ, may be of
limited benefit. The results shown here suggest that airways dysfunction remains intact
despite significantly reduced pulmonary eosinophilia
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MacKenzie, Jason Roderick. "The role of eosinophils in the regulation of CD4+ T helper 2 regulated inflammation /." View thesis entry in Australian Digital Theses Program, 2004. http://thesis.anu.edu.au/public/adt-ANU20051007.121844/index.html.
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Powell, Michael D. "Insights Into the Regulatory Requirements for T Follicular Helper Cell Development." Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/89085.
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During the course of an immune response, CD4+ T helper cells differentiate into a number of subsets including: T helper 1 (TH1), TH2, TH17, and T follicular helper (TFH) populations. The functional diversity of CD4+ T effector cells results in a coordinated, pathogen-specific immune response. For example, the production of IFNγ by TH1 cells is vital for the clearance of intracellular pathogens, while TFH cell engagement with cognate B cells is required for germinal center (GC) formation and the generation of pathogen- and vaccine- induced antibody production. The development of CD4+ subsets is contingent on extracellular signals, in the form of cytokines, and downstream transcriptional networks responsible for promoting the unique gene expression profile for each subset while simultaneously suppressing alternative cell fates. However, the exact composition of, and stage-specific requirements for, these environmental cytokines and transcription factor networks in the governance of TFH cell differentiation remain incompletely understood. The work in this dissertation seeks to understand how cell-extrinsic cytokine signals and cell-intrinsic transcription factor activities are integrated to properly regulate TFH cell development. Here, we demonstrate that in response to decreased IL-2 and constant IL-12 signaling, T helper 1 (TH1) cells upregulate a TFH-like phenotype, including expression of the TFH lineage defining transcription factor Bcl-6. Intriguingly, our work established that signals from IL-12 were required for both the differentiation and function of this TFH-like population. Mechanistically, IL-12 signals are propagated through both STAT3 and STAT4, leading to the upregulation of the TFH associated genes Bcl6, Il21, and Icos, correlating with increased B cell helper activity. Conversely, exposure of these TFH-like cells to IL-7 results in the STAT5-dependent repression of Bcl-6 and subsequent inhibition of the TFH phenotype. Finally, we describe a novel regulatory mechanism wherein STAT3 and the Ikaros zinc finger transcription factors Ikaros and Aiolos cooperate to regulate Bcl-6 expression in these TFH-like cells. Collectively, the work in this dissertation significantly advances our understanding of the regulatory mechanisms that govern TFH cell differentiation, setting the basis for the rational design of novel immunotherapeutic strategies and increasingly effective vaccines.Ph. D.
Specialized cells called T helper cells serve as a critical interface between the innate (first line of defense) and adaptive (specialized and long-term) immune systems. During the course of an infection, T helper cells are responsible for orchestrating the immune-mediated elimination of invading viruses, bacteria, and parasites. This wide breadth of functionality is achieved through the formation of distinct T helper subsets including T helper 1 (TH1), TH2, TH17, and T follicular helper (TFH) populations. Individual subsets have distinct developmental requirements and have unique functions within the immune system. For example, TFH cells are required for the production of effective antibodies that recognize invading pathogens, leading to their subsequent elimination. This naturally occurring process is the basis for a number of modern medical therapies including vaccination. Conversely, aberrant generation of antibodies that recognize host tissues can result in the onset of various autoimmune diseases including lupus, multiple sclerosis, and crohn’s disease. Due to the importance of TFH cells to human health, there is intense interest in understanding how these cells are formed. It is recognized that the generation of these therapeutically important immune cells is mediated by numerous cell-extrinsic andintrinsic influences, including proteins in their cellular environment called cytokines, and important proteins inside of the cell called transcription factors. However, as this is a complicated and multi-step process, many questions remain regarding the identity of these cytokines and transcription factors. The work in this dissertation seeks to understand how cellextrinsic cytokine signals and cell-intrinsic transcription factor activities are integrated to properly regulate TFH cell development. Collectively, this body of work significantly advances our understanding of the regulatory mechanisms that govern TFH cell differentiation, setting the basis for the rational design of novel immunotherapeutic strategies and increasingly effective vaccines.
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Mayer, Johannes Urban. "Induction of T helper 2 cell responses against Schistosoma mansoni eggs in the murine intestine." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/7972/.
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T helper 2 (Th2) cell responses typify the immune response to parasitic organisms, which frequently invade the intestine. Dendritic cells (DCs) are considered vital for the induction of Th2 responses as they present parasite- derived antigens to naive T cells in draining lymph nodes. However, the identities of the DC populations responsible for priming Th2 cells in the intestine are still unclear. We developed an experimental immunization protocol to deliver Schistosoma mansoni eggs into the intestine. During live infection by the parasite, these eggs cause intestinal damage, granuloma formation, tissue fibrosis and strong type 2 immune responses. Many aspects of type 2 immunity are controlled by the transcription factor IRF4 and we observed that intestinal Th2 responses against Schistosoma mansoni eggs did not develop in the draining lymph nodes in the absence of IRF4+ DCs. IRF4f/f CD11c-cre positive mice had fewer CD11b-expessing migrating DCs, and fewer parasite antigen-carrying DCs were present in the mesenteric lymph nodes (MLNs) draining the small intestine and colon. However, transfer of antigen-loaded IRF4-deficient DCs directly into the MLN revealed that these cells could induce antigen-specific Th2 responses, suggesting that IRF4 controlled the migration of CD11b-expessing DCs rather than their Th2 inducing capacity. Furthermore, immature DCs from the intestinal lamina propria, and semi-mature DCs from lymph were sufficient to prime antigen-specific Th2 responses against egg antigens when transferred into naive recipient mice. This induction was dependent on MHCII expression but not on the production of IL-4 by the transferred DCs, indicating that conventional intestinal DCs are fully capable of inducing Th2 responses against S. mansoni egg antigens upon transfer. Further analysis of migratory small intestinal and colonic lymph DCs revealed that distinct subsets of CD11b-expressing DCs were sufficient for the induction of Th2 responses in the small intestine and colon. CD11b+CD103+ DCs transported parasite antigen from the small intestine, whereas CD11b+CD103- DCs performed this role in the colon. Of note, these same small intestinal and colonic DC subsets were also the populations that were most efficient at priming antigen-specific Th2 responses in vivo. Thus, we have not only identified that IRF4-dependent CD11b-expressing DCs are specialized to drive Th2 responses in the intestine but have also revealed that different DC subsets promote Th2 responses in the small intestine and colon. These findings not only advance our knowledge of intestinal Th2 responses against parasite antigens but also reveal a hitherto unappreciated functional heterogeneity among intestinal DCs, which could also be relevant for other tissue- specific intestinal conditions like Crohn’s disease, ulcerative colitis and celiac disease.
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Dumont, Larry Joe. "Human cytomegalovirus reactivation following seasonal allergen exposure and switch to T-helper cell type 2 profile /." Connect to full text at ProQuest Digital Dissertations. IP filtered, 2005.
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Thesis (Ph.D. in Clinical Sciences) -- University of Colorado at Denver and Health Sciences Center, 2005.Typescript. Includes bibliographical references (leaves 140-156). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Molinder, Karen Marie. "Galectin-1 effects on development and function of CD4+ T helper cells /." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=1709046691&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Townsend, Michael John. "Investigating the In vivo roles of interleukin-9 and T1/ST2 in T helper 2 cell responses." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621375.
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Ahyi, Ayélé-Nati. "The role of PU.1 and IRF4 interaction in the biology and function of T helper 2 cells." Connect to resource online, 2009. http://hdl.handle.net/1805/1882.
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Thesis (Ph.D.)--Indiana University, 2009.Title from screen (viewed on August 26, 2009). Department of Microbiology and Immunology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Mark Kaplan. Includes vita. Includes bibliographical references (leaves 107-125).
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Bharath, Krishnan Nair Sreekumar. "The Role of IkZF Factors in Mediating TH1/TFH Development and Flexibility." Diss., Virginia Tech, 2020. http://hdl.handle.net/10919/96583.
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The ability of cells within the adaptive immune system to develop into specialized subsets allow for a robust and tailored immune response in the advent of an infection or injury. Here, CD4+ T-cells are a crucial component within this system, with subsets such as TH1, TH2, TH17, TFH and TREG cells playing vital roles in propagating cell-mediated immunity. For example, TH1 cells are essential in combating intracellular pathogens such as viruses, while TFH cells communicate with B-cells to optimize antibody responses against an invading pathogen. The development (and functionality) of these subsets is ultimately dictated by the appropriate integration of extracellular cues such as cytokines with cell intrinsic transcription factors, thereby promoting the necessary gene profile. Moreover, the observation that T-helper cells could exhibit a flexible nature (i.e having shared gene profiles and effector functions) not only demonstrate the efficiency of our immune system but also how such flexibility could have unintended consequences during adverse events such as autoimmunity. An important mediator of such flexibility is cytokines. However, the complete network of factors that come together to co-ordinate cytokine mediated plasticity remain unknown. Thus, the work in this dissertation hope to delineate the factors that collaborate to regulate cytokine induced T-helper cell flexibility. As such, we see that in the presence of IL-2, the Ikaros Zinc Finger (IkZF) transcription factor Eos is upregulated in TH1 cells, with this factor playing a significant role in promoting regulatory and effector functions of TH1 cells. Moreover, we show that Eos forms a novel protein complex with STAT5 and promotes STAT5 activity in TH1 cells. However, depleting IL-2 from the micro-environment leads to the upregulation of two other members within the IkZF family, Ikaros and Aiolos. Aiolos in turn collaborate with STAT3, induces Bcl-6 expression within these cells, thus promoting these cells to exhibit characteristic features of TFH cells. The work in this dissertation hopes to advance our understanding of the regulatory mechanisms involved in cytokine mediated T-cell flexibility thereby hoping to open new avenues for the development of novel therapeutic strategies in the event of autoimmunity.Ph. D.
T-helper (TH) cells are an important component of the immune system, as these cells aid in the fight against pathogens by secreting factors that either accentuate the inflammatory response during infection or attenuate immune responses post infection. Such effects are made possible because T-helper cells can differentiate into a variety of subsets, with each subset being an important mediator in maintaining immune homeostasis. For example, the T-helper cell subset called TH1 plays a vital role in the fight against intracellular pathogens such as viruses and certain parasites, while T-follicular helper (TFH) cells aid in the production of antibodies specific to the invading pathogen. The development of such subsets occur when cell extrinsic signals, called cytokines, lead to the activation or induction of cell intrinsic proteins called transcription factors. Interestingly, research over the years have shown that T-helper cells are highly adaptable in nature, with one subset having the ability to attain certain characteristic features of other subsets. This malleable nature of T-helper cells relies on several factors, with cytokines within the micro-environment being an important one. Although this form of flexibility is efficient and beneficial at times, it can also be detrimental, as such flexibility is known to promote certain autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and type 1 diabetes. Such detrimental effects are thought to be due to cytokines within the environment. Therefore understanding how cytokines influence the flexible nature of T-helper cells is important; as controlling such flexibility (either by regulating cytokines or the transcription factors activated as a consequence) could prevent the propagation of undesired T-helper cell functions. As such, the work in this dissertation hopes to uncover how one such cytokine, termed Interleukin-2 (IL-2) mediates the flexibility between TH1 and TFH cells. The work highlighted in this dissertation broadens our understanding of how cytokines influence T-helper cell development and flexibility, and consequently allows the design of novel therapeutic strategies to combat autoimmune diseases.
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Singh, Randeep. "Early growth response genes 2 and 3 are potent inhibitors of T-bet function for interferon gamma production in T-cells." Thesis, Brunel University, 2016. http://bura.brunel.ac.uk/handle/2438/14780.
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Early growth response (Egr) gene 2 and 3 are genes encoding transcription factors important for maintaining immune homeostasis. Here we define a fundamental role of Egr2 and 3 to control T cell proliferation and differentiation of effector T cells. Egr2 and Egr3 deficiency in T cells resulted in impaired T cell proliferation, but hyper-activation and excessive differentiation of T cells in response to viral infection, while, conversely, sustained Egr2 expression enhanced proliferation, but severely impaired effector differentiation in to T helper (Th) subsets, such as, Th1 and Th17 subtypes. T-bet is important for differentiation of effector T cells in response to pathogen and in particular it is a master regulator for modulating the T helper 1 lineage specific differentiation programme. Although T-bet has been extensively studied in T cells, the regulation of T-bet function is less well known. We have now discovered that Egr2 and 3 are potent inhibitors for Tbet function in CD4 and CD8 effector T cells. Together with Egr2 and 3, T-bet is induced in naïve T cells by antigen stimulation, but the expression was reciprocally regulated by IFNγ, which inhibited Egr2 and 3, but promoted Tbet expression. The expression of Egr2 and 3 in CD4 T cells under TH2 and TH17 condition was essential to suppress TH1 differentiation in vitro. In response to viral infection, sustained Egr2 expression in T cells profoundly inhibited differentiation of effector cells, while Egr2 and 3 deficient T cells produced excessive levels of IFNγ. We found that both Egr2 and 3 can directly interact with the Tbox domain of T-bet, block its DNA binding and inhibit T-bet mediated production of IFNγ. Thus, Egr2 and 3 are antagonists for T-bet function in effector T cells and essential for the control of T cell differentiation and immune pathology.
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Benary, Manuela. "Modeling the Interleukin 2 gene expression in activated T cells." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2016. http://dx.doi.org/10.18452/17437.
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Interleukin 2 (IL-2) ist ein Zytokin, welches in menschlichen Gedächtnis-T-Helfer-Zellen (Teff Zellen) exprimiert und sekretiert wird und damit die Immunantwort formt. Im Gegensatz dazu wird IL-2 normalerweise nicht in regulatorischen T-Zellen (Treg Zellen) exprimiert, sondern von diesen nur aufgenommen. Durch die Aktivierung des T-Zellrezeptors werden Signalkaskaden induziert, welche zur Aktivierung der Transkriptionsfaktoren AP-1, NFAT, und NF-kB führen. Diese sind entscheidend für die Genexpression von IL-2. Im Rahmen meiner Dissertation habe ich die Regulation der IL-2 Genexpression untersucht. Dabei vergleiche ich die transkriptionelle Regulation in Teff Zellen mit der Regulation in Treg Zellen. Insbesondere konnte ich zeigen, dass die endogene Konzentration der Transkriptionsfaktoren sich auf die Anzahl der IL-2 Produzenten auswirkt, aber nicht auf die Konzentration von IL-2 innerhalb einer Zelle. Deshalb untersuche ich wie sich die Konzentration der Transkriptionsfaktoren auf die Häufigkeit von IL-2 Produzenten auswirkt. Ich nutze die vorhandenen endogenen Konzentrationen und kann damit vorhersagen, dass die Zahl der IL-2 Produzenten entscheidend von der c-fos Konzentration in Teff Zellen abhängt. Mit Hilfe des entwickelten Modells kann ich voraussagen, wie der spezifische Inhibitor U0126 die Häufigkeit von IL-2 Produzenten verringert. Diese Vorhersage wurde durch Experimente belegt. Meine Modelle zeigen weiterhin, dass c-fos und NFATc2 die Häufigkeit der IL-2 Produzenten in Teff Zellen kooperativ regulieren. In Treg-Zellen zeigt meine Analyse, dass alle Transkriptionsfaktoren eine ähnliche sigmoidale Wirkung auf die Häufigkeit der IL-2-Produzenten ausüben. Im Gegensatz zu den Teff Zellen haben alle Transkriptionsfaktor eine ähnliche maximale Wirkung auf Genexpression von IL-2. Mittels eines Inhibitionsmodelles konnte ich zeigen, dass der Treg zellspezifische Transkriptionsfaktor FoxP3 allen aktivierenden Transkriptionsfaktoren entgegenwirkt.Interleukin 2 (IL-2) is a cytokine expressed in human memory T helper cells (Teff cells) and the secretion of IL-2 shapes the immune response. In contrast, human regulatory T-cells (Treg cells) commonly do not express IL-2. The gene expression of IL-2 is induced by the activation of the T-cell receptor signaling network activating the transcription factors AP-1, NFAT, and NF-kB. These transcription factors are crucial for initiating IL-2 gene expression. Within my thesis I compare the regulation of IL-2 gene expression in Teff cells and Treg cells using experiments and modeling. I demonstrate that the transcription factor concentrations correlate with number of IL-2 producers but do not affect IL-2 concentration per cell. Thus, I investigate how the transcription factor concentration of c-fos, NFATc2, p65, and p-c-jun affects the frequency of IL-2 producing cells as a proxy for the probability of a cell to produce IL-2. Using the endogenous heterogeneity of transcription factor concentrations, I predict that the number of IL-2 producers is critically dependent on the amount of c-fos in Teff cells. I use my model to predict how perturbations of c-fos by the specific inhibitor U0126 decrease the frequency of IL-2 producers in Teff cells. This prediction was than validated by experiments. My models furthermore indicate the cooperative behavior of c-fos and NFATc2 on the level of frequency of IL-2 producers in Teff cells. In Treg cells, I show that all transcription factors exert a similar sigmoidal effect on the frequency of IL-2 producers. In contrast to the effects seen in Teff cells, all transcription factor have a similar maximal effect on the IL-2 gene expression. With an inhibitory model I explore the relation between the Treg cell-specific transcription factor FoxP3 the transcription factors c-fos, NFATc2, p65, and p-c-jun on the frequency of IL-2 producers. This model indicates that FoxP3 counteracts the activating function of NFATc2, AP-1, and also NF-kB.
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Scott, Melissa Margaret Eve Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Determination of the mechanisms of immune system regulation of inflammation by the human protein, Chaperonin 10." Awarded by:University of New South Wales. Biotechnology & Biomolecular Sciences, 2009. http://handle.unsw.edu.au/1959.4/44736.
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Chaperonin 10 (Cpn10) is a mitochondrial protein with protein folding function. There is substantial evidence that extracellular Cpn10 regulates the immune response. Prior research has shown that Cpn10 binds to T cells, inhibits LPS-induced RAW264.7 macrophage cell- and healthy donor peripheral blood mononuclear cell (PBMC)-activation, and downregulates lipopolysaccharide (LPS)-induced membrane distribution of the MHC II molecule on dendritic cells (DC). Recent Phase IIa rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS) clinical trials demonstrate improved disease amelioration with Cpn10. Despite compelling evidence of the anti-inflammatory properties of Cpn10, the precise mechanisms of action are unknown. The principal aim was to characterise the modulation of inflammation by Cpn10 and in the process create a bioassay that would allow for the reliable assessment of batch-to-batch variability of Cpn10 preparations. For this purpose, a Cpn10 bioassay was performed in the RAW264.7 cell line and expanded to DC and T cell lines. Furthermore, the analysis of gene expression in healthy donor PBMC was performed, as a mixed cell population experiment, to reflect possible involvement of cell-to-cell communication pathways. Initial data showed that Cpn10 reduced LPS-induced tumour necrosis factor ?? (TNF??) expression in RAW264.7 cells. However, the Cpn10 preparation was shown to contain trace lipid contaminants, which induced cellular tolerance, resulting in the observed reduction in TNF??. Experiments with a second batch of Cpn10 showed no reduction of LPS-induced TNF?? in the RAW264.7 cells, seen with the primary batch of Cpn10 and previously reported characterisation of Cpn10. The Cpn10 bioassay conducted in DC and T cell lines was shown to have the potential to decrease toll-like receptor 9 (TLR9) expression, suggesting that Cpn10 may attenuate immune responses by downregulating receptor recognition of bacterial components. The Cpn10 bioassay conducted in LPS-stimulated PBMCs revealed that Cpn10 downregulates gene expression of Th1 related genes including the polarising cytokines IL-7, IL-12B and IL-23A and Th2 related genes including the transcriptions factors GATA3, GFI1 and CEBPB. The downregulation of these genes may play an immuno-modulatory role, having improved efficacy of Cpn10 in T cell mediated autoimmune diseases, with possible therapeutic implications in Th2 mediated diseases such as asthma. The research carried out in this thesis provides insight into the success of Cpn10 in the RA, MS and psoriasis clinical trials. These results have also supported previously published data and provide additional insight into the mechanism of action of Cpn10. In addition, a Cpn10 bioassay has been established using healthy donor PBMCs stimulated with LPS and results show a reduced expression of Th1 and Th2 associated genes. The findings that in mixed cell populations, Cpn10 downregulates not only genes involved in Th1 polarisation mainly at the signal 3 level, but is also capable of downregulating Th2 polarising genes at the signal 1 level of TCR mediated transcription factors, are of particular interest. Ultimately, research from this project has confirmed the anti-inflammatory action of Cpn10 and given useful insight into how Cpn10 acts to modulate the inflammatory response.
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Carsillo, Mary Elizabeth. "Mechanisms of Measles Virus-Induced Immune Suppression in the Cotton Rat Model." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1249584349.
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CAMPOS, Patrícia Isabel Figueiredo. "Characterization of T follicular helper (Tfh) cells and B cell isotype switching induced by type 1 and type 2 adjuvants." Master's thesis, Instituto de Higiene e Medicina Tropical, 2016. http://hdl.handle.net/10362/20059.
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A principal função dos linfócitos T CD4+ é fornecer apoio a outras células no sentido de gerar uma resposta imunitária eficiente. As interações entre as células T e B são essenciais para a produção de respostas humorais, sendo que foi recentemente demonstrado que as células T foliculares auxiliares (Tfh) desempenham um papel crucial neste processo. Caracteristicamente, expressam o fator de transcrição Bcl-6, o recetor de quimiocinas CXCR5 e o marcador de superfície PD-1. A expressão destes marcadores é única e fundamental para que estas células possam aceder ao folículo de células B, onde orientam as reações no centro germinativo (GC), levando à consequente mudança de isótipo, maturação da afinidade, produção de anticorpos de alta afinidade e células B de memória.
Neste projeto, foram testadas duas hipóteses opostas no sentido de caracterizar fenotipicamente as células Tfh. Propomos investigar se estas são especializadas no fornecimento de auxílio do tipo Th1 ou Th2, que designamos de células hipotéticas "Tfh1" e "Tfh2" (Hipótese 1) ou se são uma subpopulação genérica que responde igualmente na presença de diferentes antigénios, células Tfh (Hipótese 2).
Deste modo, murganhos C57BL/6J e Balb/c foram imunizados na almofada plantar da pata traseira, utilizando proteína Ovalbumin (OVA) combinada com diferentes tipos de adjuvantes: CpG ODNs isoladamente e em combinação com TiterMax® Gold (TMX), Sigma Adjuvant System (SAS) e Montanide ISA 720 VG, testados como adjuvantes tipo 1, e por sua vez Incomplete Freund’s Adjuvant (IFA) e Alum experimentados como adjuvantes do tipo 2. A técnica de ELISA permitiu determinar no soro dos murganhos o tipo de resposta gerada, através da medição de imunoglobulinas específicas para OVA (IgG2a para Th1, IgG1 e IgE total para Th2). CpG ODNs e IFA foram considerados como os adjuvantes mais apropriados para induzir respostas Th1 e Th2, respetivamente.
Células T que reconhecem especificamente OVA foram colhidas de murganhos OT-II Rag-/- e DO11.10 Rag-/- e transferidas para murganhos congénicos. De seguida, procedeu-se à imunização tal como descrito acima. Os nódulos linfáticos drenantes foram recolhidos no pico da reação do centro germinativo (11 dias após imunização), assim como as células Tfh específicas para OVA (CD4+CD44+ CXCR5+PD-1+ Thy1.2+Vβ5+Vα2+/DO11.10+) e as células T auxiliares ativadas específicas para OVA (CD4+CD44+CXCR5-PD-1- Thy1.2+Vβ5+Vα2+/DO11.10+).
A caracterização molecular destas populações de células T está a ser analisada através da sequenciação dos seus transcritos pela técnica de RNA-sequencing. Além disso, a expressão de marcadores de Th1 e Th2 em células Tfh foi analisada através de citometria de fluxo e Reação em Cadeia da Polimerase quantitativa por Transcrição Reversa (RT-qPCR). Neste estudo, foi demonstrado que as células Tfh co-expressam Bcl-6 e T-bet e também produzem IFN-γ, quando sensibilizadas com OVA-CpG ODNs, características concordantes com os marcadores fenotípicos de uma célula Tfh e célula Th1. A expressão de Gata-3 (marcador Th2) só foi detetada sob estimulação IFA-OVA, embora em níveis mais baixos do que as determinadas para T-bet.The major function of CD4+ T cells is to provide help to other lymphocytes to mount an efficient immune response. T and B cell interactions are essential for humoral responses and it was recently shown that T follicular helper (Tfh) cells play a crucial role in this process. They characteristically express the transcription factor Bcl-6, chemokine receptor CXCR5 and PD-1. These markers are unique as their expression is pivotal to acquire access to the B cell follicle and drive germinal centre (GC) reactions, leading to isotype switching, affinity maturation, and production of high affinity antibodies and memory B cells. In this project, two competing hypothesis investigating the phenotype of Tfh cells were tested. We propose to dissect whether Tfh cells are specialized in providing Th1 or Th2 help, which we call putative “Tfh1” and “Tfh2” cells (hypothesis 1), or if they are a more generic Th subset that responds equally in the presence of different antigens, which we designate as Tfh cells (hypothesis 2). Therefore, we immunized C57BL/6J and Balb/c mice in the footpad using Ovalbumin (OVA) protein combined with different adjuvant types: CpG ODNs only and combined with TiterMax® Gold (TMX), Sigma Adjuvant System (SAS) and Montanide ISA 720 VG, as type 1 adjuvant, and Incomplete Freund’s Adjuvant (IFA) and Alum as type 2 adjuvants. Using ELISA assays to determine the type of response generated by measuring serum immunoglobulins of distinct clones (OVA-specific IgG2a for Th1 and OVA-specific IgG1 and total IgE for Th2), we considered CpG ODNs and IFA as the most appropriate adjuvants to induce Th1 and Th2 responses, respectively. OVA-specific cells were transferred from OT-II Rag-/- and DO11.10 Rag-/- mice into congenic mice subsequent to immunization as described above. Draining LNs were collected at the peak of the GC reaction (day 11 post-immunization) and OVA-specific Tfh cells (CD4+ CD44+ CXCR5+PD-1+ Thy1.2+Vβ5+Vα2+/DO11.10+) and OVA-specific activated-Th cells (CD4+ CD44+ CXCR5-PD-1- Thy1.2+Vβ5+Vα2+/DO11.10+) were sorted. The molecular signature of these T cell populations is being analysed via RNA-Sequencing. Moreover, the expression of Th1 and Th2 markers on Tfh cells was investigated via flow cytometry and Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR). In this study, it could be shown that Tfh cells of mice immunized with OVA-CpG ODNs co-expressed Bcl-6 and T-bet and also produced IFN-γ, both concordant features with the phenotypic markers of a Tfh cell and of a Th1 cell. As for the expression of Gata-3, it has only been detected in mice under IFA-OVA stimulation, even though at levels lower than the ones determined for T-bet.
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Sánchez-Guajardo, Vanesa María. "Kinetics and competitive capacities of Th1 vs. Th2 CD4+ T cells : the role of Stat6 and Stat4 in CD4+ T cell homeostasis." Paris 6, 2005. http://www.theses.fr/2005PA066547.
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Jacquemin, Clément. "Modulation de la balance lymphocytaire T régulatrice et effectrice dans deux modèles de maladies auto-immunes." Thesis, Bordeaux 2, 2013. http://www.theses.fr/2013BOR22050.
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Le respect de l’équilibre entre lymphocytes T effecteurs auto-réactifs et lymphocytes T régulateurs (LTreg) est primordial dans le maintien de la tolérance aux antigènes du soi. Les partenaires cellulaires et les mécanismes moléculaires impliqués dans la rupture de l’équilibre de cette balance ne sont pas ou peu connus dans les maladies auto-immunes. Ainsi, les travaux décrits dans cette thèse portent sur le dérèglement de la balance T effecteurs/ Treg dans deux modèles de maladies auto-immunes chez l’homme: le lupus érythémateux systémique et l’anémie hémolytique auto-immune (AHAI). Nous montrons une augmentation de l’expression de la molécule de costimulation OX40L (CD252, TNFSF4) à la surface des cellules présentatrices d’antigène circulantes et infiltrant les tissus chez les patients lupiques. Cette augmentation est corrélée à l’activité de la maladie chez l’adulte comme chez l’enfant. Elle a pour conséquence l’induction de lymphocytes T effecteurs de type Tfh (T follicular helper) et le blocage des fonctions suppressives des Treg, deux acteurs majeurs dans la physiopathologie du lupus. Dans le second projet, nous montrons une augmentation de la proportion de T8reg circulants chez les patients affectés d’une AHAI à anticorps chauds en phase de rémission. Ces Treg expriment le CD25, le FoxP3 et exercent leur fonction suppressive par un mécanisme faisant intervenir l’IL10. De faibles doses d’IL-2 permettent l’expansion de cette population cellulaire in vitro. Ces résultats apportent de nouvelles connaissances dans la physiopathologie de ces deux maladies et offrent des perspectives thérapeutiques potentiellesRespect of the balance between autoreactive T cells and regulatory T cells (LTreg) is important to maintain tolerance to self-antigens. Cellular partners and molecular mechanisms involved in the disruption of this balance are not or little known in autoimmune diseases.Thus, the work described in this thesis focuses on the disruption of the T effector/ Treg balance in two models of human autoimmune diseases: systemic lupus erythematosus and autoimmune hemolytic anemia (AIHA). We show an increased expression of the OX40L (CD252, TNFSF4) costimulatory molecule at the surface of both circulating and tissues-infiltrating antigen presenting cells in SLE patients. OX40L expression is correlated with disease activity in adults and in children and results in Tfh (follicular helper T) effector cells induction and Treg suppressive functions inhibition, two key mechanisms in the pathogenesis of lupus. In the second project, we show an increase of the circulating T8reg proportion in patients with a warm AIHA in a non-active state. These Treg express CD25, FoxP3 and exert their suppressive function by a mechanism involving IL-10. Low-dose IL-2 allows the expansion of this cell population in vitro. These results provide new insights into the pathophysiology of these diseases and offer potential therapeutic perspectives
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Viardot, Alexander Garvan Institute of Medical Research Faculty of Medicine UNSW. "The role of insulin, peptide YY and the immune system in the pathogenesis of type 2 diabetes." Publisher:University of New South Wales. Garvan Institute of Medical Research, 2008. http://handle.unsw.edu.au/1959.4/42886.
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Obesity and type 2 diabetes (T2D) are associated with insulin resistance and increased levels of inflammation markers, suggesting activation of the immune system. However, the link between this so called ??low-grade inflammation?? and insulin resistance is poorly understood. In this thesis we aimed to investigate the direct effects of insulin on immune cells, and if these effects are changed in the setting of insulin resistance. We showed that insulin has anti-inflammatory effects by shifting T cell differentiation into a T helper type 2 phenotype. This effect was lost in insulin resistant subjects, which resulted in a more pro-inflammatory T helper type 1 cell hyperpolarisation. We also demonstrated that the Th1/2 balance is related to the degree of insulin resistance, and varies accordingly in clinical models of increasing or decreasing insulin resistance. Furthermore, we demonstrated that in a very early stage of pre-diabetes, where normal glucose tolerance and insulin sensitivity are still preserved, we cannot detect any immune activation, but we see a blunted food response of the appetite suppressant hormone PYY. Whilst this could put subjects at risk for further weight gain and development of obesity and T2D, we also demonstrated for the first time that PYY itself has strong anti-inflammatory properties, and that a deficiency in PYY could result in promoting a pro-inflammatory environment. In summary, we could demonstrate strong evidence that both, insulin and PYY are potent anti-inflammatory hormones which modulate immune function, and the observed deficiency in these hormones could contribute to further increase in inflammation and disease progression. Further work is indicated in this area to better understand the sequence and mechanism of immune activation, which may open up new therapeutic avenues for prevention and treatment of T2D.
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Renand, Amédée. "La neuropiline 1 et le récepteur alpha à l’IL-2 (CD25) : expression et implication dans l’homéostasie des lymphocytes T chez l’homme dans un contexte normal ou pathologique." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T032/document.
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Des études récentes ont montré une implication de la neuropiline 1 (Nrp1)dans le contrôle de l’activation des lymphocytes T. Son invalidation s’accompagne d’une aggravation de l’encéphalite auto-immune expérimentale (EAE). La sémaphorine 3A (Sema-3A), ligand principal de la Nrp1, semble participer à une boucle autocrine de rétro contrôle négatif de la prolifération des lymphocytes T.Cependant, peu d’études ont été réalisées chez l’homme pour déterminer dans quelle(s) situation(s) la Nrp1 est exprimée par les lymphocytes T. Notre travail aconsisté à étudier l’expression de la Nrp1 par les populations lymphocytaires T humaines afin de comprendre à quel niveau peut avoir lieu ce rétro contrôle. Nous montrons que les lymphocytes T régulateurs (Treg) chez l’homme n’expriment pas laNrp1, contrairement aux Treg murins. En revanche, la Nrp1 est exprimée par les lymphocytes T effecteurs après engagement avec l’antigène, soit au niveau des organes lymphoïdes secondaires pour les lymphocytes T folliculaires helper (Tfh) en interaction avec les lymphocytes B, soit au niveau des sites d’inflammations périphériques pour les lymphocytes T effecteurs mémoires (TEM). Dans les deux cas, cette expression survient en fin d’activation et pourrait servir de frein à une activation incontrôlée des lymphocytes T.D’autre part, nous avons abordé le rôle du récepteur alpha à l’IL-2 (CD25)dans l’homéostasie des lymphocytes T. L’étude chez la souris il2ra-/- a révélé un rôle important du CD25 pour la survie des Treg in vivo, mais aussi pour l’acquisition de lymphocytes T mémoires. Seulement deux cas de déficience en CD25, associés à des maladies auto-immunes, ont été décrits chez l’homme. Cependant, ces études n’ont pas abordé à quel niveau le CD25 intervient sur l’homéostasie des lymphocytes T. Nous complétons ces études par la présentation de trois nouveaux cas de déficience en CD25 développant des maladies auto-immunes de type IPEX. Nous montrons que le CD25 intervient activement dans le maintien des populations Treg naïves et effectrices, mais aussi dans celui des populations lymphocytaires effectrices mémoiresRecent studies have shown the involvement of neuropilin 1 (Nrp1) in the control of T cell activation, and disruption of this receptor promotes aggravation of experimental autoimmune encephalitis (EAE). Through its principal ligand,semaphorin 3A (Sema-3A), Nrp1 appears to participate in an autocrine negative feedback of T cell proliferation. However, few studies have been conducted inhumans to determine when Nrp1 is expressed by T cells. Here we show that regulatory T cells (Treg) in humans do not express Nrp1, unlike murine Treg cells. In contrast, we show that Nrp1 is expressed by effector T cells after engagement with antigen, either in secondary lymphoid organs for follicular helper T cells (Tfh) interacting with B cells, either in peripheral inflammation for effector memory T cells(TEM). We conclude that this expression corresponds to a level of late activation in both cases and may control T cell activation.The study in mice il2ra-/- revealed a significant role of IL-2 receptor alpha(CD25) for the survival of Treg in vivo, but also for the differentiation of memory T cells. Only two cases of CD25 deficiency associated with autoimmune diseases have been described in humans. However, these studies do not assess at what levelCD25 is involved in T cell homeostasis. Here we provide further insight of these studies by presenting three new cases of CD25 deficiency developing autoimmune diseases like IPEX. We show that CD25 plays an active role to maintain naive and effector Treg cell populations of, and effector memory T cell populations
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French, Anne Thérèse. "The co-regulation of the mucus associated molecules intelectin, resistin like molecule beta and beta galactoside alpha 2-3 sialyltransferase in a T helper cell type 2 response." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/28071.
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The mucus associated molecules intelectin (ITLN), resistin like molecule beta (RELMβ) and beta galactoside alpha 2-3 sialyltransferase (SIAT4C) are upregulated in nematode infections known to induce a typical T helper cell type 2 (Th2) response in mice. It was hypothesised that these three mucus-associated molecules were co-regulated by Th2 cytokines and that their upregulation was part of a typical anti-parasite response in other species. Sheep were chosen as a model because of the economic importance of both respiratory and gastrointestinal tract parasitic infections. Culture of a human colonic carcinoma cell line with either interleukin 4 (IL-4) or IL-13 confirmed the upregulation of ITLN and RELMβ in a Th2 environment however failed to show co-regulation with SIAT4C. Of the Th1 or Th2 cytokines examined only IFNγ had a significant effect on expression of SIAT4C transcript. ITLN transcript and protein was demonstrated in sheep tissue and furthermore three different ITLNs (sITLN1, sITLN2, sITLN3) which had a differential tissue distribution were cloned and sequenced. SIAT4C was widely expressed in sheep tissues and the full sequence was deduced. There was no evidence of expression of RELMβ sITLN transcripts were upregulated in response to IL-4 in an ex-vivo sheep tracheal explant culture model whilst sheep (s) SIAT4C was significantly downregulated in the same model. In a sheep model of infection with the abomasal nematode, Teladorsagia circumcincta, known to induce a Th2 biased response, sITLN transcripts and protein and sSIAT4C transcript were upregulated in response to a challenge infection. sITLN1 and sITLN2 were shown to upregulate at an earlier time point post challenge in previously infected (immune) compared to naïve yearling sheep and lambs and significant upregulation of sSIAT4C transcript was seen in challenged previously infected but not challenged naïve sheep and lambs. sITLNs and sSIAT4C may have an important role in the mucosal immune response to parasitic infections in sheep.
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Abelius, Martina S., Jan Ernerudh, Göran Berg, Leif Matthiesen, Lennart Nilsson, and Maria Jenmalm. "High cord blood levels of the T-helper 2-associated chemokines CCL17 and CCL22 precede allergy development during the first 6 years of life." Linköpings universitet, Pediatrik, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-74499.
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Exposure to a strong T-helper 2 (Th2)-like environment during fetal development may promote allergy development. Increased cord blood (CB) levels of the Th2-associated chemokine CCL22 were associated with allergy development during the first 2 y of life. The aim of the present study was to determine whether CB Th1- and Th2-associated chemokine levels are associated with allergy development during the first 6 y of life, allowing assessment of respiratory allergic symptoms usually developing in this period. The CB levels of cytokines, chemokines, and total IgE were determined in 56 children of 20 women with allergic symptoms and 36 women without allergic symptoms. Total IgE and allergen-specific IgE antibody levels were quantified at 6, 12, 24 mo, and 6 y of age. Increased CB CCL22 levels were associated with development of allergic sensitization and asthma and increased CCL17 levels with development of allergic symptoms, including asthma. Sensitized children with allergic symptoms showed higher CB CCL17 and CCL22 levels and higher ratios between these Th2-associated chemokines and the Th1-associated chemokine CXCL10 than nonsensitized children without allergic symptoms. A pronounced Th2 deviation at birth, reflected by increased CB CCL17 and CCL22 levels, and increased CCL22/CXCL10 and CCL17/CXCL10 ratios might promote allergy development later in life.
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Nath, Puneeta. "Investigation of T-helper type 2 cytokines and the mitogen-activated protein kinase pathway in the modulation of bronchial hyperresponsiveness, airway inflammation and remodelling." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417857.
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Ogbe, Ane Theodora. "Early Growth Response genes 2 and 3 play a role in chronic inflammation pathology and are essential for the differentiation of T follicular helper cells." Thesis, Brunel University, 2015. http://bura.brunel.ac.uk/handle/2438/11214.
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The Early Growth Response genes 2 and 3 (Egr2/3) are zinc finger transcription factors that play an important role in the immune system. These transcription factors have reported functions in T cell receptor signaling, differentiation of effector T cell subsets and the development of lupus-like autoimmune diseases. Using CD2-Egr2-/- Egr3-/- mouse model, I investigate the development of inflammation pathology, differentiation of T follicular helper (Tfh) cells and the formation of germinal centers (GC) following viral challenge within these mice. The onset of inflammation pathology in CD2-Egr2-/- Egr3-/- mice was discovered to correlate with high levels of pro-inflammatory cytokines in the serum and the development of autoimmune diseases as previously reported by Li et al, 2012. Most importantly, a novel role for the Egr2/3 genes in the differentiation of T follicular helper (Tfh) cells was identified. Tfh cells are responsible for T cell dependent antibody immune response in the GC. They support the differentiation of GC B cells into plasma cells producing long lived high-affinity isotype-switched antibodies and memory B cells. Tfh cell differentiation is regulated by Bcl6 however; the regulators of Bcl6 during Tfh differentiation remain largely unknown. We have now discovered that Egr2/3 genes are required for Bcl6 expression during Tfh cell differentiation. In the absence of the Egr2 and 3 genes, Tfh cell differentiation is severely impaired and GC formation and functions were defective in response to Vaccinia Virus Western Reserve strain (VVWR) infection. Further investigation revealed that Egr2 regulated Bcl6 expression in a Tfh-specific manner as adoptive transfer of WT CD4+ T cells into Egr2-/- Egr3-/- mice was able to rescue Bcl6 expression, Tfh differentiation and GC formation. When the molecular mechanism of how Egr2 regulated Bcl6 was investigated, it was uncovered that Egr2 directly bound to the promoter region of Bcl6 gene in CD4 T cells to regulated Bcl6 expression. Indeed constitutive expression of either Egr2 or Bcl6 in CD2-Egr2-/- Egr3-/- CD4+ T cells rescued Tfh cell differentiation and GC formation. Our results inferred that the Egr2/3 genes are essential for Tfh differentiation and GC formation by regulating Bcl6 expression in CD4 T cells under Tfh condition. Our studies thus suggest that the Egr2/3 genes are paramount for minimising immunopathology and are also critical for efficient antibody production by regulating Tfh cell differentiation.
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Johnson, Deborah K. "The Effects of Immune Regulation and Dysregulation: Helper T Cell Receptor Affinity, Systemic Lupus Erythematosus and Cancer Risk, and Vaccine Hesitancy." BYU ScholarsArchive, 2020. https://scholarsarchive.byu.edu/etd/9199.
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Helper T cells direct the immunological response to foreign pathogens and cancer. To become activated, helper T cells must recognize unique peptides presented on major histocompatibility complex II (pMHCII) by antigen presenting cells (APCs) with their T cell receptor (TCR). While much is known about helper T cell activation signaling cascades and the subsequent roles of helper T cell subsets, the initiation of helper T cell activation by the TCR and other co-receptors is less well understood. Specifically, the affinity of the TCR for its pMHCII can change helper T cell subset fate, proliferation, and alter the risk for activation induced cell death. High affinity TCRs are attractive targets for immunotherapies, but little is known about how helper T cells respond to high affinity TCRs. Here we describe high affinity TCR activation thresholds for both full length TCRs and chimeric antigen receptor TCRs both with and without the presence of the coreceptor CD4 and propose a mechanism whereby CD4 inhibits T cell activation via Lck sequestration and a CD4-independent method. Dysregulated helper T cells play critical roles in the development and perpetuation of systemic lupus erythematosus (SLE), a systemic autoimmune disease that causes widespread inflammation and organ damage throughout the body. Chronic inflammation in SLE affects the immune response to viruses and the risk of developing cancer. However, in SLE patients, it is unclear if viruses initiate the development of cancer directly or if the effects are non-interacting and concomitant. Here we describe the interactions between SLE, viruses, and cancer risk revealing that viruses and SLE do interact to increase the both the overall cancer risk and the risk for hematological malignancies. Due to vaccine efficacy, vaccine preventable diseases (VPDs) are no longer commonly experienced or understood by the public. Vaccines are a victim of their own success and according to the World Health Organization (WHO), vaccine hesitancy (VH) is one of the top threats to global health. VH is the refusal to accept vaccinations and the reasons for VH vary across time, place, and vaccine. Refuting VH is difficult as directly confronting false assumptions can cause individuals to become more entrenched in their position resulting in confirmation bias. Adults with VH attitudes are often motivated by concerns over personal liberty, harm, independence, and body purity. Here we describe the results of a VPD interview- and education-based intervention geared towards promoting positive vaccine attitudes for young adults and demonstrate that education focused on VPDs is more effective than vaccine safety.
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Arima, Hiroshi. "B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell-dominant T cell responses via IL-33." Kyoto University, 2019. http://hdl.handle.net/2433/236612.
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Karpf, Léa. "Systematic Study of OX40 Ligand Context-Dependent Function on Human T Helper Cell Polarization A Quantitative Multivariate Model of Human Dendritic Cell-T Helper Cell Communication TH Cell Diversity and Response to Dupilumab in Patients With Atopic Dermatitis Inborn Errors of Type I IFN Immunity in Patients With Life-Threatening COVID-19 Quantitative Modeling of OX40 Ligand Context-Dependent Function on Human T Helper Cell SARS-CoV-2 Induces Activation and Diversification of Human Plasmacytoid Pre-Dendritic Cells." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL044.
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L'immunité adaptative est principalement orchestrée par des lymphocytes T CD4 auxiliaires. Ils ont la capacité de se polariser en plusieurs sous-populations, chacune associée à un phénotype approprié au pathogène rencontré. L'activation des lymphocytes T auxiliaires peut être régulée par des checkpoints immunitaires co-stimulateurs, tel que OX40 Ligand, ou co-inhibiteurs. Ces molécules ont été étudiées individuellement, dans des conditions spécifiques. Cependant, la contexte-dépendance pourrait expliquer une grande partie de la variabilité fonctionnelle des biomolécules. Il n'y a actuellement aucune méthode permettant d’analyser et de quantifier la contexte-dépendance d’une molécule dans plusieurs contextes et sur une réponse donnée.Mon projet de thèse a porté sur la fonction de OX40L sur la polarisation des cellules T auxiliaires, dans 4 contextes moléculaires et 11 cellulaires. Nous avons mesuré 17 cytokines T auxiliaires et développé une stratégie de modélisation statistique pour quantifier la contexte-dépendance deOX40L. Les scores de contexte-dépendance se sont révélés très variables qualitativement et quantitativement, en fonction de la cytokine et du type de contexte. Parmi les contextes Th, Th2 était le plus influent sur la fonction OX40L. Parmi les contextes DC, le type de cellules dendritique était dominant dans le contrôle de la contexte-dépendance de OX40L plutôt que le stimuli d’activation. Mon travail de thèse dévoile les complexes déterminants de la fonction de OX40L, fournit une méthode unique pour quantifier la variabilité fonctionnelle contexte-dépendante de n’importe quelle biomolécule et appuie sur le fait que la contexte-dépendance devrait être davantage prise en considération dans les études futuresAdaptive immunity is mainly orchestrated by CD4 T helper cells. They have the ability to polarize in several subsets, each associated to a suitable phenotype for the encounter pathogen. T helper cell activation can be regulated by co-stimulator, such as OX40 Ligand, or co-inhibitor immune checkpoint molecules. These molecules have been studied individually, in specific conditions. However, context-dependency may explain large parts of the functional variability of biological molecules on a given output. Currently, there is no framework to analyze and quantify context-dependency of a molecule over multiple contexts and response outputs. My PhD project focused on OX40L function on T helper cell polarization, in 4 molecular and 11 cellular contexts. We measured 17 T helper cytokines and developed a statistical modeling strategy to quantify OX40L context-dependency on these cytokines. This revealed highly variable qualitative and quantitative context-dependency scores, depending on the output cytokine and context type. Among molecular contexts, Th2 was the most influential on OX40L function. Among cellular contexts, dendritic cell type rather than activating stimulus was dominant in controlling OX40L contextdependency. My thesis work unveils the complex determinants of OX40L function, provides a unique framework to quantify the context-dependent functional variability of any biomolecule, and supports that context-dependency should be more taken into consideration in future studies
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Ribeiro, Camila Maria Beder 1982. "Caracterização clínica-histológica e estudo de polimorfismos das respostas T-Helper-1 e 2 (Th1/2) nas doenças imunologicamente mediadas com manifestações bucais = líquen plano oral e reação liquenóide oral por amálgama dental." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/289239.
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Orientador: Jacks Jorge JuniorTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: As lesões liquenóides orais (LLO), como líquen plano oral (LPO) e reação liquenóide oral por amálgama dental (RLO-AD), são doenças imunologicamente mediadas (DIM) com características histopatológicas semelhantes, porém com prognósticos distintos. As suas etiopatogenias têm sido relacionadas a polimorfismos gênicos e secreção citocinas de inflamatórias (CI), as quais são responsáveis pelas respostas imunológicas inadequadas, que causam danos estruturais à mucosa oral (MO) e estimulam o recrutamento de células inflamatórias. Assim, foi realizado um estudo em voluntários portadores de LLO (grupo-1, n=39), em voluntários saudáveis (grupo-2, n=39), e em cem amostras de DNA provenientes de voluntários saudáveis (grupo-3, n=100). A pesquisa teve como objetivos selecionar e diferenciar casos de LLO clássicas (LLO-c) por meio dos critérios de diagnósticos de LLO da Organização Mundial de Saúde (Cdx-LLO-OMS); determinar a hipossalivação nesses pacientes; analisar outros achados histopatológicos presentes nas LLO; quantificar linfócitos T (LT-CD3, LT-CD8), linfócitos B (LB), plasmócitos, mastócitos, imunomarcados contidos no infiltrado inflamatório subepitelial (IISE) nos casos de LLO a fim de avaliar as respostas Th1/2; e estimar a frequência dos polimorfismos dos genes Th1/2 envolvidos na síntese de CI através da reação em cadeia da polimerase (PCR) e polimorfismo no comprimento do fragmento de restrição (RFLP). De forma geral, pacientes do gênero feminino com idade média de 53,13 anos apresentaram maior frequência de LLO (p=0,06; OR:2,57). O infiltrado inflamatório perivascular profundo e a presença de folículos linfóides foram frequentes nas RLO-AD (p<0,001). A contagem de LB foi maior nas RLO-AD (p<0,05). A hipossalivação foi frequente em portadores de LLO (p<0,001;OR:19,72). Os alelos mutados IL4-590T,TNF-?-308A, e IL10592C foram freqüentes nos portadores de LLO (p<0,0001). Portadores de LPO apresentaram mais alelos mutados IL4-590T e IL10-592C (p<0,05). Concluiu-se, portanto que pacientes do gênero feminino com média de idade de 53 anos apresentam mais LLO. A hipossalivação foi associada à presença da lesão oral em portadores de LLO. As LLO estão associadas aos altos índices de células de reação inflamatória crônica e à expressão gênica das citocinas relacionadas às respostas Th1/2
Abstract: Oral lichenoid lesions (OLL), such as oral lichen planus (OLP) and amalgam-associate oral lichenoid reaction (AAOLR) are immunologically mediated diseases (IMD) with similar histopathologic features but distinct prognoses. Their etiopathogenesis have been related to gene polymorphisms and inflammatory cytokine (IC) secretion, which are responsible for the inappropriate immune responses that cause structural damage to the oral mucosa (OM) and stimulate the recruitment of inflammatory cells. Therefore, this study was conducted in a group of volunteers with OLL (group-1, n=39), another group comprised of healthy volunteers (group-2, n=39), and a third group comprised of hundred DNA samples obtained from healthy volunteers (group-3, n = 100). The research aimed to select and differentiate classic cases of OLL by means of diagnostic criteria for OLL of the World Health Organization (WHO-OLL-CDx), to determine the hyposalivation in these patients, to analyze other histological findings features present in OLL; to evaluate the Th1/2 by means of quantification of inflammatory cells, T-lymphocytes (CD3-TL, CD8-TL), B lymphocytes (BL), plasma cells and mast cells immunostained contained in the subepithelial inflammatory infiltrate (SEII) on the slides of OLL, and estimate the frequency of polymorphisms of genes Th1/2 involved in the synthesis of IC by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Overall, female patients with mean age of 53.13 years had a higher frequency of OLL (p = 0.06, OR: 2.57). The deep perivascular inflammatory infiltrate and lymphoid follicles were common in the AAOLR (p <0.001). The LB count was higher in AAOLR (p <0.05). The hyposalivation was common in patients with OLL (p <0.001, OR: 19.72). Mutated alleles of IL4-590T, TNF-?-308A and IL10-592C were frequent in patients with OLL (p <0.0001). Patients with OLP had more mutated alleles IL4 and IL10-590T-592C, when compared to AAOLR (p <0.05). Therefore it was concluded that female patients with a mean age of 53 have more OLL. Hyposalivation was associated with the presence of oral lesions in patients with OLL. The oral lichenoid lesions are associated with high rates of chronic inflammatory cell reaction and gene expression of cytokines related to Th1/2 response
Doutorado
Patologia
Doutor em Estomatopatologia
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Hu, Jian. "L'etude de la regulation de l'activation de clones de lymphocytes t humains helpers et cytotoxiques par les molecules cd2." Paris 7, 1988. http://www.theses.fr/1988PA077078.
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Ricard, Laure. "Les lymphocytes T folliculaires auxiliaires dans la sclérodermie systémique." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS340.
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La sclérodermie systémique (SSc) est une maladie auto-immune, caractérisée par une atteinte microvasculaire oblitérante, de la fibrose et des anomalies de l'immunité humorale. Les lymphocytes T folliculaires auxiliaires (Tfh) CD4+CXCR5+PD1+ coopèrent avec les lymphocytes B pour induire leur différenciation en plasmocytes sécréteurs d’immunoglobulines (Ig). Les Tfh circulants (cTfh) sont augmentés dans plusieurs maladies auto-immunes et les Tfh infiltrent la peau des patients SSc. Nous avons observé que les cTfh des patients SSc étaient augmentés en comparaison avec les témoins et notamment dans des formes sévères de SSc. Les cTfh des patients SSc ont un phénotype activé avec une forte expression de BCL-6 et des capacités augmentées à produire de l’IL-21. In vitro, les cTfh de patients SSc sont aussi plus efficaces pour stimuler la différenciation des plasmablastes (PB) ainsi que leur production d’Ig. Le blocage de l’IL-21 ainsi que le ruxolitinib, un inhibiteur de la voie JAK1/2 diminuaient la capacité des cTfh à stimuler la différenciation des PB et leur sécrétion d’Ig. Les mécanismes à l’origine de cette expansion aberrante des cTfh dans la SSc demeurent à définir. Les cellules dendritiques, les monocytes ainsi que des anomalies épigénétiques pourraient être à l’origine de cette expansion des cTfh. L’hématopoïèse clonale (HC) est définie par l’acquisition de mutations somatiques dans les cellules souches hématopoïétiques menant à des clones détectables. Nous avons observé une forte prévalence d’HC dans la SSc. Le gène le plus fréquemment muté était DNMT3A impliqué dans la régulation épigénétique. Le rôle de ces mutations dans la physiopathologie de la SSc reste à démontrerSystemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis, vascular microangiopathy and deregulated immune system with the presence of autoantibodies. Follicular helper T (Tfh) cells, defined as CD4+CXCR5+PD-1+ cooperate with B lymphocytes to induce the differentiation of plasmocytes secreting immunoglobulins (Ig). Circulating Tfh (cTfh) cells are increased in several autoimmune diseases, and Tfh cells can infiltrate the skin of SSc patients. We demonstrate that cTfh cell are increased in SSc patients compared with healthy controls (HC), which was more potent in severe forms of SSc. cTfh cells from SSc patients present an activated Tfh phenotype, with high expression of BCL-6 and increased capacity to produce IL-21 in comparison to HC. In vitro, cTfh cells from SSc patients had higher capacity to stimulate the differentiation of plasmablasts and their secretion of Ig through the IL-21 pathway. Blocking IL-21 or using the JAK1/2 inhibitor (ruxolitinib) reduced the Tfh cells’ capacity to stimulate the plasmablasts and decreased the Ig production. Mechanisms leading to this aberrant cTfh expansion remain to be established. Monocytes and dendritic cells could participate to this cTfh expansion. Epigenetics abnormalities could also contribute to cTfh activation in SSc. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the acquisition of somatic mutations in hematopoietic stem cells leading to detectable clones. We observed a high prevalence of CHIP in SSc patients. The most common mutation occurred in DNMT3A gene involved in epigenetic regulation. The implication of these mutations in SSc pathophysiology remains to be demonstrated
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Marschall, Pierre. "Etude de la fonction des cellules dendritiques dans la réponse immunitaire cutanée de type 2." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ044.
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La dermatite atopique (AD) est une des maladies inflammatoires chroniques cutanée les plus fréquentes qui affecte jusqu'à 20% des enfants et 3% des adultes dans le monde. Elle se caractérise par une inflammation chronique de la peau et des réponses immunitaires humorale et de type 2. Mon travail de thèse est d'étudier le rôle des cellules dendritiques (DCs) dans la génération des lymphocytes T et la pathogenèse de l'AD. Dans la partie I, à l'aide de deux modèles murins d'AD, l'un déclenché par la surexpression de TSLP dans la peau induite par l'application topique de MC903 et l'autre par sensibilisation à un allergène à travers une peau dont la barrière épidermique est lésée, nous montrons le rôle crucial joué par TSLP dans la différentiation des lymphocytes T auxiliaires folliculaires (Tfh) et le développement des centres germinatifs (GC). Nous établissons le rôle contradictoire des cellules de Langerhans dans la réponse Tfh/GC promue par TSLP. Dans la partie II, nous montrons que, en plus de son implication dans la réponse Th2, TSLP signale par son récepteur TSLPR à la surface des DCs pour induire la différentiation des lymphocytes Tregs ST2+ dans le ganglion drainant. De plus, la différentiation de ces cellules implique OX40L, molécule de costimulation exprimée par certaines DCs migratoires, suggérant que l'axe TSLP-TSLPRDC-OX40L joue un rôle non reconnu dans l'induction des lymphocytes Tregs ST2+ dans le cadre de l'ADAtopic dermatitis (AD) is a one of the most common chronic inflammatory skin disease which affects up to 20% of children and 3% of adults worldwide, with increasing prevalence in the industrialized countries during the last 30 years. It is characterized by chronic cutaneous inflammation, humoral and T helper type 2 (Th2) responses. My PhD study is to investigate the role of skin dendritic cells (DCs) in the generation of T helper cells in the pathogenesis of AD. In the Part I, using two mouse models of AD, one triggered by the overexpression of TSLP in mouse skin through topical application of MC903, and the other one with epicutaneous allergen sensitization on barrier-disrupted skin, we demonstrated a crucial role of TSLP in promoting T follicular helper (Tfh) cell differentiation and germinal center (GC) response. We uncovered a seemingly contradictory role of Langerhans cells in TSLP-promoted Tfh/GC response. In the part II, we showed that, in addition to promote Th2 cell differentiation, TSLP signals through TSLPR expressed by DCs to induce the differentiation of ST2+ Tregs in skin-draining lymph nodes. Interestingly, the differentiation of these cells implicates OX40L, a costimulatory molecule expressed in a subset of migratory DCs, suggesting a previously unrecognized role of TSLP-TSLPRDC-OX40L axis in the induction of ST2+ Tregs in AD pathogenesis
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Müller-Hilke, Brigitte. "Die differentielle Expression von MHC II-Genen als Mechanismus bei der Entstehung von Autoimmunerkrankungen." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2000. http://dx.doi.org/10.18452/13720.
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Protektive MHC II Allele sind sowohl für den Menschen als auch für die Maus beschrieben worden und verhindern die Entstehung von Autoimmunerkrankungen. Hier untersuche ich die differentielle Expression von MHC II Allelen auf den unterschiedlichen Antigen-praesentierenden Zellen als Wirkmechanismus, der das Typ 1-Typ 2 Gleichgewicht der T-Helferzellen beeinflusst. Ich konnte zeigen, dass die als protektiv geltenden murinen I-Ab und I-Ek Molekuele auf fast allen Knochenmark-Makrophagen fuer 5 - 8 Tage stark exprimiert werden und dass die Expression dann langsam abnimmt. Im Gegensatz dazu fanden wir eine etwa 100-fach schwaechere Expression des mit der Kollagen-induzierten Arthritis (CIA) assoziierten I-Aq. Diese Expression war von nur kurzer Dauer und nahm rasch ab. Eine aehnlich differentielle Expression konnten wir weder auf B- noch auf dendritischen Zellen (DZ) nachweisen. Zusätzlich konnte in in vitro Restimulationsexperimenten gezeigt werden, dass Makrophagen durch diese differentielle Expression die T-Zell-Zytokinantwort massgeblich beeinflussen. Unsere Ergebnisse deuten an, dass Makrophagen eines protektiven Haplotyps MHC II Molekuele in hoher Zahl exprimieren und damit bevorzugt Typ 1 Antworten hervorrufen, wohingegen eine niedrige MHC II Expression Typ 2 Antworten beguenstigt. Wir schliessen daraus, dass das Ausmass der MHC II Expression das Signal, welches von den T-Zellen zu den Makrophagen zurückgesendet wird, steuert und damit die Aktivitaet der Makrophagen reguliert. Dieser durch polymorphe, jedoch nicht-kodierende MHC II-Gensegmente hervorgerufene Effekt koennte bei der Empfaenglichkeit fuer Autoimmunerkrankungen sowohl beim Menschen als auch bei der Maus eine Rolle spielen. Tatsaechlich konnten wir auch auf menschlichen Monozyten und B-Zellen eine differentielle Expression von HLA II Genen nachweisen und sie scheint sich hier auf die nur gering-polymorphen DRB4 Gene, die sowohl mit dem Rheumatoide Arthritis (RA) assoziierten DR4 als auch mit dem neutralen DR7 koexprimiert werden, zu beschraenken. In meinem letzten Teil ziele ich darauf ab, das den Verlauf der RA und der CIA begleitende Typ 1 Übergewicht in ein Gleichgewicht mit Typ 2 zu revertieren. Dazu wurde ein Mausmodell etabliert, bei dem bereits polarisierte Typ 2 Th-Effektorzellen als Manipulatoren der für die Entstehung der CIA verantwortlichen, Kollagen-spezifischen Typ 1 Zellen eingesetzt wurden. Tatsaechlich konnte die CIA dann am effektivsten verhindert werden, wenn beide T-Zellpopulationen, die Manipulierer und die Kollagen-spezifischen, im selben Zellcluster aktiviert wurden. Diese Aktivierung im selben Zellcluster konnte dadurch erreicht werden, dass DZ gleichzeitig Kollagen und das fuer die Manipulierer spezifische Epitop praesentieren.Protective/suppressive MHC class II alleles have been identified in man and mouse where they exert a disease-protective and immunosuppressive effect. As a mode of action we here investigate differential expression of MHC class II genes in different types of antigen-presenting cells impacting on the Type 1-Type 2 balance. We found that the murine I-Ab and I-Ek molecules, both well characterized as protective/suppressive, are expressed at a high level on almost all bone marrow derived macrophages for five to eight days after which expression slowly declines. In contrast, the collagen-induced arthritis (CIA) associated I-Aq-expression is lower, peaks over a shorter period and declines more rapidly. No differential expression could be detected on B cells or dendritic cells (DC). In addition, the differential MHC class II expression found on macrophages skews the cytokine response of T cells as shown by an in vitro restimulation assay. The results indicate that macrophages of the protective/ suppressive haplotypes express MHC class II molecules at a high level and exert Type 1 bias whereas low level expression favors a Type 2 response. We suggest that the extent of expression of the class II gene gates the back-signal from T cells and in this way controls the activity of macrophages. This effect mediated by polymorphic non-exon segments of MHC class II genes may play a role in determining disease susceptibility in mouse and man. Indeed, we also found differential expression of HLA II genes on human antigen presenting cells. However, in humans, differential expression affects both, B cells and monocytes and seems to be restricted to the non-polymorphic DRB4 gene coexpressed with the rheumatoid arthritis (RA) associated DR4 and the neutral DR7. We finally aimed at reverting the Type 1 bias characteristic of RA and CIA. A murine system was developed where polarized Type 2 cells were used to manipulate collagen II-specific type 1 T cells responsible for the development of collagen induced arthritis. The polarized inducer cells indeed exerted their maximum effect when the two T-cell populations were activated within the same cluster, implemented by allowing a single DC to present both their epitopes.
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Jenks, Scott. "LFA-1 costimulation inhibits T helper type 2 differentiation /." 2001. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3006514.
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Altin, John Andrew. "On the regulation of T helper type 2 (Th2) responses." Phd thesis, 2012. http://hdl.handle.net/1885/150819.
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"Helper T cells are required for normal immune function and act by marshalling the activity of other immune cell types. Their biology is dominated by a paradigm in which cells adopt mutually antagonistic functional specializations following their activation. One such specialization, adopted by ""T helper type 2 (Th2)"" cells, is characterized by the production of cytokines including IL-4 that drive a response dominated by the production of IgG and IgE antibodies, and the recruitment of innate inflammatory cells such as mast cells, basophils and eosinophils. A response of this kind mediates protection against extracellular parasites such as helminths, but can also underlie the maladaptive reaction to innocuous non-self antigens that appears central to the etiology of allergy. The possibility for this latter deleterious kind of immune response motivates the work presented in this thesis.
In particular, this thesis addresses the following question: how is the Th2 response regulated? Put another way: what cellular and molecular constraints ensure that Th2 cells do not expand inappropriately? In general, the regulation of helper T cell responses is known to occur by mechanisms that act within effector T cells (""cell-intrinsic"") as well as those that are mediated by other cell types (""cell-extrinsic""). Regulatory mechanisms can also be classified according to whether they operate before a response had developed (""anticipatory""), or emerge only as a consequence of inflammatory activation (""feedback""). Rather than focus a priori on any one of these modes of regulation, or on any particular molecular or cellular pathway, an unbiased experimental approach was adopted here. To this end, inbred mice carrying point mutations induced in a genome-wide fashion by the chemical mutagen ethyl-nitroso urea (ENU) were studied. Since Th2 responses are normally undetectable in naive C57BL/6 mice, genetic variant mice in which such responses were spontaneously evident were of interest, as they were taken to embody a failure of Th2 regulation. The work presented here began with the study of two ENU-generated strains that showed preliminary evidence of Th2 dysregulation in the form of spontaneously elevated serum IgE and dermatitis. Cellular analysis confirmed that that these phenotypes - which result from point mutations in the genes Card11 and Ndfip1 respectively - are associated with striking, spontaneous expansion of Th2 cells.
This thesis describes the study of these mutants to define three new pathways of Th2 regulation: (a) a cell-extrinsic anticipatory pathway mediated by Foxp3+ Tregs and sensitive to inherited partial loss of TCR/CD28-Card11 signaling (chapter 3), (b) a cell-intrinsic feedback pathway regulated by Ndfip1 and the cytokine IL-4 (chapter 4), and (c) a cell-extrinsic feedback pathway mediated by differentiation of effector Th2 cells into a novel cell type, the Th2 inhibitory 'Th2i' cell (chapter 5)."
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Tavares, Bárbara Estefânia da Silva Pereira Nogueira. "HIV-2 ability to infect Human Follicular T helper cells." Master's thesis, 2017. http://hdl.handle.net/10316/83320.
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Dissertação de Mestrado em Biologia Celular e Molecular apresentada à Faculdade de Ciências e TecnologiaAcquired Immunodeficiency Syndrome (AIDS) is caused by two types of virus: HIV-1 orHIV-2. Much less attention has been given to HIV-2 infection because this epidemic ismostly confined to West Africa and some non-African countries, as is the case ofPortugal. HIV-2 infection is characterized by a slow rate of CD4+ T cell loss and low levelsof viral RNA in plasma, which clinically translates into a much longer asymptomaticphase and a slower progression rate AIDS, in comparison with infection by HIV-1. Recentstudies have shown that follicular helper T cells (Tfh) represent largest main cellreservoir of HIV-1. These cells play a key role in the formation of the germinal centers insecondary lymphoid tissues, as well as in the subsequent selection, survival anddifferentiation of B cells with the ability to produce high-affinity antibodies. There arecurrently no data on Tfh in HIV-2 infection. The main objective of this study was toevaluate whether HIV-2 is able to infect Tfh. For this purpose, tonsils discarded duringroutine tonsillectomy were used as a source of secondary lymphoid tissue, and an invitro assay of infection of purified cells was optimized. Different CD4 T cell subsets wereinfected with primary isolates of HIV-2 and HIV-1, using different co-receptors (CXCR4or CCR5). For the first time, we showed that HIV-2 is able to infect Tfh, although the Tfhlevels of proviral DNA were lower than those found upon HIV-1 infection performed inparallel. Moreover, Tfh were able to support viral replication, with an increase in totalproviral DNA levels occurring 48 hours after stimulation of the infected cells and withevidence of non-defective viruses in the culture supernatants. Together, these resultscontribute to a better understanding of HIV-2 infection, revealing new insights into theability of the virus to infect Tfh cells with new targets being identified for viral replicationcontrol.
A Síndrome da Imunodeficiência Adquirida (SIDA) é provocada por dois tipos de vírus:HIV-1 ou HIV-2. Tem sido dada muito menos atenção à infeção por HIV-2 por estaepidemia estar confinada maioritariamente à África Ocidental e a alguns países nãoAfricanos, como é o caso de Portugal. A infeção pelo HIV-2 caracteriza-se por um ritmolento de perda de células T CD4 e baixos níveis de ARN viral no plasma. Clinicamentetraduz-se numa longa fase assintomática e numa progressão mais lenta para odesenvolvimento de SIDA, relativamente à infeção por HIV-1. Estudos recentes têmvindo a demonstrar que as células T foliculares auxiliares (Tfh) representam um dosmaiores reservatórios de HIV-1. Estas células têm um papel fundamental na formaçãodos centros germinativos dos tecidos linfoides secundários, bem como na subsequenteseleção, sobrevivência, diferenciação de células B em células capazes de produziranticorpos de alta afinidade. Este trabalho teve como principal objetivo avaliar acapacidade do HIV-2 para infetar as Tfh. Para isto, foi usado tecido linfoide de amígdalasretiradas por indicação clínica e otimizado um protocolo de infeção in vitro de célulaspurificadas. Diferentes populações celulares de células T CD4 foram infetadas comisolados primários de HIV-2 e HIV-1, usando diferentes co-recetores (CXCR4 ou CCR5).Demonstrámos pela primeira vez que as Tfh são infetáveis pelo HIV-2, ainda que osníveis de DNA proviral total tenham sido inferiores aos obtidos nas infeções pelo HIV-1efetuadas em paralelo. Mostrámos ainda que estas células são capazes de suportar areplicação viral, tendo-se verificado um aumento dos níveis de DNA proviral total, 48horas após estimulação das células infetadas e comprovado a existência de vírus nãodefetivos nos sobrenadantes das culturas. Em conclusão, estes resultados contribuempara o melhor entendimento da infeção por HIV-2, revelando novos conhecimentossobre a capacidade do vírus infetar as células Tfh, tendo sido identificado novos alvospara o controle da replicação viral.
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TSUNG-YUN, HOU, and 侯宗昀. "Role of Enhancer of Zeste Homolog 2 on T Helper Cell-Mediated Allergic Inflammation." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/tpuh68.
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博士國防醫學院
醫學科學研究所
105
Enhancer of zeste homolog 2 (Ezh2) has been proposed to affect the differentiation of T helper (Th) 1 and 2 cells through mice studies using Ezh2-deficient T cells. Nevertheless, the results have been varying, and the role of Ezh2 in human Th1 and Th2 cell differentiation and its association with allergic disease remains unknown. To explore the potential involvement of Ezh2 in allergic inflammation, we measured the expression of Ezh2 in Th1 and Th2 cells using flow cytometry in peripheral blood mononuclear cells in patients with allergic rhinitis and controls. We also evaluated the alteration of the expression of Ezh2 in Th1 and Th2 cells after acute challenge with house dust mite. Furthermore, the role of Ezh2 was further investigated by adding the p38 inhibitor to see if this affected allergen-induced Th1 and Th2 differentiation. We found the expression of Ezh2 in the Th1 and Th2 cells was significantly lower in the patients than in the controls, and was negatively correlated with serum IL-17A levels in the patients. Ex-vivo house dust mite allergen challenge resulted in rapid Th2 cell differentiation, which was negatively associated with the Ezh2 expression in Th2 cells. In contrast, Th1 cell differentiation seemed positively associated with the Ezh2 expression in Th1 cells. Inhibiting p38 activity increased the expression of Ezh2 in Th2 cells and reduced the number of differentiated Th2 cells. Our findings suggest that Ezh2 expression is potentially associated with allergic rhinitis development. Changes in the expression of Ezh2 may influence Th1/2 cell differentiation and the subsequent development of allergic disease.
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MacKenzie, Jason Roderick. "The Role of Eosinophils in the Regulation of CD4+ T helper 2 Regulated Inflammation." Phd thesis, 2003. http://hdl.handle.net/1885/47792.
Full textAbstract:
The eosinophil is a leukocyte whose intracellular mediators are considered to play a central role in the pathogenesis of allergic diseases, including allergic asthma, allergic rhinitis and atopic dermatitis, and which is also involved in immunological responses to parasites. Eosinophil differentiation and maturation from bone marrow progenitors is regulated by interleukin-5 (IL-5), which may be secreted by T helper 2 (Th2) T lymphocytes, and is consistently upregulated in allergic conditions. Eotaxin is a potent chemoattractant for circulating and tissue eosinophils, and the production of this chemokine promotes eosinophil infiltration and accumulation within sites of allergic inflammation.¶ ...¶ In conclusion, eosinophils residing in the allergic lung have the capacity to interact with activated T cells, both within this tissue and the draining lymph nodes. Despite their relative inefficiency as antigen presenting cells (Mawhorter et al., 1994), eosinophils may participate en masse in the serial triggering of activated TCRs, and provide appropriate costimulatory signals that modulate T lymphocyte function. Through the elaboration of Th2 cytokines and stimulation of T cell proliferation, antigen presenting eosinophils may transiently prolong or exacerbate the symptoms of allergic diseases. Alternatively, eosinophils presenting relevant antigens may inhibit T cell activity via degranulation, and such activity has recently been observed in a parasite model (Shinkai et al., 2002). Finally, experiments in the OT-II mouse have provided valuable information to suggest that therapies designed to modulate eosinophil numbers in allergic tissues through the secretion of opposing cytokines such as IFN-γ, may be of limited benefit. The results shown here suggest that airways dysfunction remains intact despite significantly reduced pulmonary eosinophilia
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Kim, Sophia Hyun. "Type 2 diabetes mellitus increases inflammation in periodontitis by promoting CD4+ T helper cell cytokine production." Thesis, 2015. https://hdl.handle.net/2144/13966.
Full textAbstract:
Periodontitis (PD) and type 2 diabetes mellitus (T2D) are chronic inflammatory diseases in which the host immune system encounters changes in its T and B cell distribution and function. Both disorders are increasingly prevalent in the U.S. and while T2D is a risk factor for periodontal disease, PD can exacerbate diabetes. Previous studies have unsuccessfully attempted to determine the underlying molecular mechanism for the relationships between T2D and periodontitis. To test directly the effect of T2D on periodontitis, I quantified cytokine production by gingival immune cells from three types of subjects: healthy, periodontal disease and T2D with periodontal disease, using single cells purified via flow cytometry and assessed for function with an enzyme-linked immunospot (ELISPOT) assay. The cells were sorted into subtypes according to CD45+, CD4+, CD8+, CD11b+, CD19+ and/or CD56+ expression, were stimulated by PMA, ionomycin or LPS, and were aliquoted into a well of a 96-well ELISPOT plate for 36 hours. Outcomes showed that CD4+ is the predominant cell population in lymphocytes and that gingiva tissues from periodontitis/T2D group produced higher concentrations of cytokines characteristic of the Th1 T cell subset, namely IL-2, IL-10, TNF-α and IFN-γ (p<0.05, <0.001, <0.001, <0.01, respectively) compared to tissues from either healthy or periodontitis group. This work illustrates that T2D increases inflammation in periodontitis through an increase in Th1 T helper cell function.
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Antig, Luis Dominick Barrozo, and 安路益. "Bioactive ingredient derived from Hirsutella sinensis mycelium attenuates T helper type 2 allergic response and asthma." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/9enf3j.
Full text
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Tseng, Chin-kun, and 曾今坤. "Transgenic and Knockout Animal-based Study on Dengue Virus Infection: Investigation of T Helper 1 and Helper 2 Development and Protective Role of NS1-specific Antibody." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/14292180098634528568.
Full textAbstract:
碩士國防醫學院
微生物及免疫學研究所
91
Dengue viruses cause a severe public health problem throughout the tropical and subtropical areas of the world. Accumulating data indicate that dengue nonstructural protein 1 (NS1) can serve as vaccine protecting mice against dengue infection. We previously demonstrated that mice vaccinated with NS1 DNA (pD2NS1) and subsequently challenged by lethal DEN-2 exhibited a delay onset of paralysis, a marked decrease of morbidity, and a significant enhancement of survival. Moreover, by using MHC class I and II knockout mice as vaccination/challenge models, we found CD8+ T cells are essential for pD2NS1 vaccination-induced protection. To further investigate the virus-induced immune responses and protective mechanisms involved in pD2NS1 immunization, we established similar vaccination/challenge models by using Th1 and Th2 double transgenic and B-cell deficient mice in this study. Mice deficient in B cells immunized with pD2NS1 still protected from subsequent viral challenge, indicating that NS1-specific antibody can be dispensable in DEN-2 NS1 DNA-mediated protection. However, compared with wild type littermates, unimmunized B-cell deficient mice showed much higher mortality after lethal viral challenge, suggesting that humoral immune response still plays certain role for host against DEN infection. In Th1 and Th2 double transgenic mice immunized with pD2NS1, there is a significant increase of CD4+ subpopulation and enhancement of Th2-type response. Similar results of increasing CD4+ cells and Th2 immunity were found in these pD2NS1-immunized mice followed by viral challenge. These results may help us to understand host immunity against DEN infection and provide further insight into vaccine development.
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Ahyi, Ayele-Nati. "The role of PU.1 and IRF4 interaction in the biology and function of T helper 2 cells." Thesis, 2009. http://hdl.handle.net/1805/1882.
Full textAbstract:
Indiana University-Purdue University Indianapolis (IUPUI)Adaptive and innate immune responses play a critical role in the protection against extracellular or intracellular pathogens. The function of these two types of immune responses is coordinated by CD4+ T-helper (Th) cells. Depending on the cytokine environment, Th progenitor (Thp) cells differentiate into three functionally different effector subsets. T-helper-1 (Th1) cells which mediate cell-mediated immunity, T-helper-2 (Th2) which orchestrates humoral immunity and T-helper-17 (Th17) cells key players in autoimmunity response. Cytokine induced transcription factors that are differentially expressed in Th cells are required for the development and commitment to a specific Th lineage. The population of Th2 cells can be subdivided in subpopulations depending on the level of a cytokine and the subsets of cytokines they produce. Very limited information is available about the regulation of cytokine production in this array of Th2 cells. We have recently identified the ETS family transcription factor PU.1 as regulating heterogeneity in Th2 populations. To define additional factors that might contribute to Th2 heterogeneity, we examined the PU.1 interacting protein IFN-regulatory factor (IRF)-4, a transcription factor expressed in lymphocytes and macrophages. When Th2 cells are separated based on levels of IL-10 secretion, IRF4 expression segregates into the subset of Th2 cells expressing high levels of IL-10. To investigate the role of IRF4 in cytokine heterogeneity, Th2 cells were infected with retrovirus expressing IRF4. The cells overexpressing IRF4 secreted significantly higher levels of IL-10 and IL-4 compared to cells infected with a control vector at the same time the level of IL-9 decreases. To understand the mechanism by which IRF4 regulates IL-10 expression in various Th2 cell subpopulations we used co-immunoprecipitation assays to determine transcription factors that interact with IRF4. Our data shows that PU.1, IRF4 and NFATc2 form a complex in Th2 nuclear extract. We also demonstrated by ChIP assay that IRF4 directly binds the Il10 and Il4 loci in a time dependent manner. The role of these protein-protein and protein-DNA complexes and their contribution towards Th2 heterogeneity will be further defined. Understanding the regulation of the anti-inflammatory cytokine IL-10 in Th2 cells may give us a tool to control inflammation.
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"Activation of human eosinophils by novel t-helper type 2 cytokine IL-33: implications for the immunopathology of allergic inflammation." 2009. http://library.cuhk.edu.hk/record=b5893986.
Full textAbstract:
Chow, Yin Sau Joyce.Thesis (M.Phil.)--Chinese University of Hong Kong, 2009.
Includes bibliographical references (leaves 127-140).
Abstract also in Chinese.
Abstract --- p.I
摘要 --- p.V
Acknowledgements --- p.VIII
Publications --- p.X
Table of contents --- p.XII
Abbreviations --- p.XV
Chapter Chapter 1: --- General Introduction --- p.1
Chapter 1.1 --- Allergic diseases and allergic inflammation --- p.1
Chapter 1.1.1 --- Allergic diseases and their prevalence --- p.1
Chapter 1.1.2 --- Immunopathology of allergic inflammation --- p.2
Chapter 1.2 --- Biology of human eosinophils --- p.4
Chapter 1.2.1 --- Morphology --- p.4
Chapter 1.2.2 --- Cell surface receptors and mediators --- p.4
Chapter 1.2.3 --- Origin and development of eosinophils --- p.7
Chapter 1.3 --- Eosinophils and allergic inflammation --- p.7
Chapter 1.3.1 --- Adhesion molecules on eosinophils for emigration --- p.8
Chapter 1.3.2 --- Eosinophil activation and inflammatory mediators --- p.13
Chapter 1.3.3 --- Survival of eosinophils in allergic inflammation --- p.18
Chapter 1.3.4 --- Immunopathological roles of eosinophils in allergic inflammation --- p.18
Chapter 1.4 --- Intracellular signaling mechanisms --- p.20
Chapter 1.4.1 --- Signal transduction pathways of eosinophils --- p.20
Chapter 1.4.2 --- Inhibitors of signaling molecules --- p.26
Chapter 1.5 --- Aim of study --- p.29
Chapter Chapter 2: --- Materials and Methods --- p.31
Chapter 2.1 --- Materials --- p.31
Chapter 2.1.1 --- Human eosinophils --- p.31
Chapter 2.1.2 --- Cell culture --- p.33
Chapter 2.1.3 --- Cell surface and intracellular immunofluorescent staining --- p.36
Chapter 2.1.4 --- Detection of cytokine and chemokine release --- p.39
Chapter 2.1.5 --- Detection of cell viability and apoptosis --- p.40
Chapter 2.1.6 --- Protein extraction --- p.40
Chapter 2.1.7 --- Western blot analysis --- p.40
Chapter 2.1.8 --- Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) --- p.42
Chapter 2.2 --- Methods --- p.45
Chapter 2.2.1 --- Purification of human eosinophils --- p.45
Chapter 2.2.2 --- Cell culture --- p.46
Chapter 2.2.3 --- Cell surface and intracellular immunofluorescent staining --- p.47
Chapter 2.2.4 --- Detection of cytokine and chemokine release --- p.48
Chapter 2.2.5 --- Detection of cell viability and apoptoas --- p.49
Chapter 2.2.6 --- Protein extraction --- p.49
Chapter 2.2.7 --- Western blot analysis --- p.50
Chapter 2.2.8 --- SDS-PAGE --- p.50
Chapter 2.2.9 --- Statistical analysis --- p.51
Chapter Chapter 3: --- Role of Novel IL-1 Family Cytokine in Allergic Inflammation: IL-33-mediated Eosinophil Activation --- p.52
Chapter 3.1 --- Introduction --- p.52
Chapter 3.2 --- Results --- p.54
Chapter 3.2.1 --- "Total protein expression of IL-33 receptor, ST2, of human eosinophils" --- p.54
Chapter 3.2.2 --- "Intracellular protein expression of IL-33 receptor, ST2，in human eosinophils" --- p.55
Chapter 3.2.3 --- "Extracellular protein expression of IL-33 receptor, ST2, on human eosinophils" --- p.56
Chapter 3.2.4 --- "Effects of IL-1β IL-18, and IL-33 on survival of human eosinophils" --- p.57
Chapter 3.2.5 --- "Effects of IL-1β, IL-18, and DL-33 on surface adhesion molecule expression on human eosinophils" --- p.60
Chapter 3.2.6 --- "Effects of IL-1β, IL-18, and IL-33 on chemokine and cytokine release from human eosinophils" --- p.64
Chapter 3.2.7 --- "Synergistic effects of IL-1β, IH8, and IL-33 on IL-6 release from human eosinophils" --- p.69
Chapter 3.2.8 --- "Effects of transcription and translation inhibitors on IL- 1β, IL-18, and IL-33-induced chemokine and cytokine release from human eosinophils" --- p.71
Chapter 3.2.9 --- "Effects of different inhibitors on lL-1β, IL-18, and IL-33-induced survival enhancement of human eosinophils" --- p.75
Chapter 3.2.10 --- Effects of different inhibitors on IL-1β and IL-33-mediated surface expression of adhesion molecules on human eosinophils --- p.77
Chapter 3.2.11 --- "Effects of different inhibitors on IL-33, IL-1β，and IL-18-induced release of CCL2，CXCL8，and IL-6 from human eosinophils" --- p.79
Chapter 3.2.12 --- "Effects of IL-33, IL-1β and IL-18 on activation of ERK, p38 MAPK, and NF-kB pathways in human eosinophils" --- p.83
Chapter 3.3 --- Discussion --- p.85
Chapter Chapter 4: --- Co-culture of Eosinophils & Epidermal Keratinocytes Upon IL-33 Stimulation: Implications for Immunopathology of Atopic Dermatitis --- p.95
Chapter 4.1 --- Introduction --- p.95
Chapter 4.2 --- Results --- p.98
Chapter 4.2.1 --- Effect of IL-33 on surface expression of CD18 and ICAM-1 upon the interaction of human eosinophils and epidermal keratinocytes --- p.98
Chapter 4.2.2 --- Effect of IL-33 on CCL2 release upon the interaction of human eosinophils and epidermal keratinocytes --- p.98
Chapter 4.2.3 --- Effect of IL-33 on CXCL8 release upon the interaction of human eosinophils and epidermal keratinocytes --- p.101
Chapter 4.2.4 --- Effect of IL-33 on IL-6 release upon the interaction of human eosinophils and epidermal keratinocytes --- p.101
Chapter 4.2.5 --- Source(s) of CCL2 in co-culture of human eosinophils and epidermal keratinocytes upon IL-33 stimulation --- p.104
Chapter 4.2.6 --- Source(s) of CXCL8 in co-culture of human eosinophils and epidermal keratinocytes upon IL-33 stimulation --- p.105
Chapter 4.2.7 --- Source(s) of IL-6 in co-culture of human eosinophils and epidermal keratinocytes upon BL-33 stimulation --- p.108
Chapter 4.2.8 --- "Effect of transwell insert on the induction of CCL2，CXCL8, and IL-6 release in co-culture of human eosinophils and epidermal keratinocytes upon IL-33 stimulation" --- p.110
Chapter 4.3 --- Discussion --- p.113
Chapter Chapter 5: --- Concluding Remarks and Future Perspectives --- p.120
Chapter 5.1 --- Concluding Remarks --- p.120
Chapter 5.2 --- Future Perspectives --- p.123
Appendix --- p.126
References --- p.127
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Chang, Chia Bin, and 張家濱. "The modulatory mechanisms of DNA demethylation agent 5-Aza-2’-deoxycytidine on T helper cell function in experimental autoimmune encephalomyelitis." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/78841618390411478691.
Full textAbstract:
碩士國立中正大學
分子生物研究所
100
Regulatory T (Treg) cells play a key role in maintaining self-tolerance and immunological homeostasis. Forkhead box P3 (Foxp3) is a transcription factor necessary and sufficient for Treg cells development and immunosuppressive function. Defective Treg suppressive functions were observed in many autoimmune diseases including multiple sclerosis. It had been reported that DNA methylation regulated the expression of Foxp3. In the previous report, treatment with low dose of DNA demethylation agent 5-Aza-2’-deoxycytidine (5-Aza) enhanced the Treg-mediated suppression and repressed the progression of diabetes in NOD mice. In this study, we investigated the treatment of 5-Aza in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for human multiple sclerosis, to evaluate the demethylation effect in autoimmune diseases. We found that treatment of 5-Aza mice delayed the onset of EAE and only displayed the mild symptoms. Moreover, we used luxol fast blue staining to observe the demyelination in central nervous system (CNS) and found that control EAE mice developed severe demyelination but 5-Aza treated mouse did not. Next, we evaluated the inflammatory responses in CNS, there was no inflammation in 5-Aza treated mice because of the very low level of inflammatory cytokines, and on the contrary, control EAE mouse expressed very high level of IFN-γ and IL-17 in the inflamed sites. Furthermore, pretreated with 5-Aza enhanced the Treg-mediated suppression in Treg inhibitory assay. However we found that suppression of effector T cell proliferation resulted from the reduced function of effector T cells but not from the enhanced function of Treg cells. Therefore, pretreatment of 5-Aza prevented demyelination, and reduced the effector T cells function and limited pathogenic lymphocyte into CNS, prompted the inhibition of experimental autoimmune encephalomyelitis.
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"THE CRITICAL ROLE OF CD4+ TH CELLS IN CD8+ CTL RESPONSES AND ANTI-TUMOR IMMUNITY." Thesis, 2012. http://hdl.handle.net/10388/ETD-2012-04-424.
Full textAbstract:
The goal of this body of research was to elucidate the mechanism by which CD4+ T cells provide help for CD8+ cytotoxic T lymphocyte (CTL) responses in different immunization types. The establishment of diseases, such as chronic infections and cancers, is attributed to severe loss of or dysfunctions of CD4+ T cells. Even in acute infections, CD4+ T cell deficiency leads to poor memory responses. While the role of CD4+ T cells is being increasingly appreciated in these diseases, the timing and nature of CD4+ T help and associated molecular mechanisms are not completely understood. Growing evidence suggests that, depending on the type of infections or immunizations, the requirements of CD4+ T cells can vary for optimal CD8+ CTL responses. In order to understand the modulatory effects of CD4+ T cells for optimal CD8+ CTL responses, two distinct immunization types were chosen. These include: 1) non-inflammatory dendritic cell (DC) immunization, which fails to provide inflammatory/danger signals; and 2) inflammatory adenovirus (AdV) immunization, which provides profound inflammatory/danger signals. This allowed us to study CD4+ T cell’s participation under different inflammatory conditions.
The studies described in Chapters 2 and 3 of this thesis were performed to further understand the concept of how CD4+ T cells mediate optimal CD8+ CTL responses. This has been called the “new dynamic model of CD4+ T helper – antigen (Ag)-presenting cells (Th-APCs),” proposed in 2005 by our laboratory. The study described in Chapter 2 shows that Th-APCs participate not only in augmenting CTL-mediated immune responses, perhaps during early phase, but also in regulating cellular immunity, perhaps during a later phase. Through enhanced IL-2, CD80 and CD40L singnaling, and weaker peptideMHC I (pMHC) signaling, Th-APCs stimulated naïve CD8+ T cells to differentiate into effector CTLs, capable of developing into, central memory CTLs. Th-APC-stimulated CD4+ T cells behaved like Th cells in function, augmenting the overall magnitude of CTL responses. In contrast, Th-APCs were able to kill DCs and other Th-APCs, predominantly through perforin-mediated pathway. The experiments described in Chapter 3 revealed a novel co-operative role of cognate Th-CTL interactions, contrary to previously known immune-regulatory mechanisms among Th-Th or CTL-CTL interactions. In our experiments, Th cells, via CD40L, IL-2, and acquired pMHC-I signaling, enhanced CTL survival and transition into functional memory CTLs. Moreover, RT-PCR, flow cytometry and western blot analysis demonstrate that increased survival of Th cell-helped CTLs is matched with enhanced Akt1/NF-κB activation, down-regulation of FasL and TRAIL, and altered expression profiles with up-regulation of prosurvival (Bcl-2) and down-regulation of proapoptotic (NFATc1, Bcl-10, Casp-3, Casp-4, Casp-7) genes/ molecules. Finally, helped CTLs were also able to induce protection against highly metastasizing tumor challenge, explaining why memory CTLs generated under cognate Th1’s help show survival and recall advantages.
The studies in Chapter 4 showed how the precursor frequency (PF) of CD8+ T cells impacts CD4+ T helper requirements for functional CTL responses. At endogenous PF, CD4+ T helper signals were necessary for both primary and memory CTL responses. At increased PF, CD4+ T help, and its CD40L but not IL-2 signal became dispensable for primary CTL responses. In contrast, memory CTL responses required CD4+ T cell signals, largely in the form of IL-2 and CD40L. Thus, these results could impact the development of novel immunotherapy against cancers, since their efficacy would be determined in part by CD4+ T help and CD8+ T cell PF.
Finally, the study showed the importance of CD4+ T cells for multiple phases of AdV transgene product-specific CTL responses. These include: a) cognate CD4+ T cells enhanced CTL responses via IL-2 and CD40L signaling during primary, maintenance and memory phases; b) polyclonal CD4+ T environment enhanced the survival of AdV-specific CTL survival, partially explaining protracted CTL contraction phase; and c) during the recall phase, the CD4+ T environment, particularly memory CD4+ T cells, considerably enhanced not only helped, but also unhelped, memory CTL expansion. Thus, these results suggest the participation of both cognate and polyclonal CD4+ T cells for multiple phases of AdV-specific CTLs.
Taken together, the current work delineated the critical roles of CD4+ T cells in different stages of CTL responses and in the development of anti-tumor immunity. The results presented here will significantly advance our current understanding of immunity to cancers, autoimmunity and chronic infections, since pathogenesis of these diseases is largely determined by CD4+ T helper functions. As most immunization procedures use the principle that is based on functions of memory cells, the knowledge gained from this work will also have a major impact on designing vaccines against intractable diseases, including cancers and chronic infections. Moreover, in advanced tumors, vaccines developed using this knowledge may act synergistically with other cancer treatments such as irradiation, chemotherapy and microsurgery, minimizing their side effects and prolonging the lives of patients.