Dissertations / Theses on the topic 'T-cell homeostasi'
To see the other types of publications on this topic, follow the link: T-cell homeostasi.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'T-cell homeostasi.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Basilissi, M. "T-CELL HOMEOSTASIS, MODIFICATIONS OF MUCOSAL IMMUNITY POPULATIONS AND ASSOCIATION WITH HIV-MEDIATE MICROBIAL TRANSLOCATION AND DYSBYOSIS: EXTENSIVE IMMUNE PHENOTYPING DURING 1 YEAR OF SUCCESSFUL COMBINATION ANTIRETROVIRAL THERAPY (CART)." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/489804.
Full textAbstract:
In the era of combination antiretroviral therapy (cART), a reduction of HIV and AIDS-comorbidities and death has been described. Nonetheless, immune defects persist during treatment and may be linked to increased morbidity and mortality of HIV-infected subjects compared to the general population.
Microbial translocation and dysbiosis as well as impaired mucosal immunity likely represent underlying pathogenic mechanisms of the peripheral immune flaws observed during therapy.
However, a systematic investigation of these parameters in a longitudinal cohort of HIV-infected individuals starting cART is currently lacking.
In this context, the overall objective of our research is to understand the extent by which enduring gut abnormalities represent a cause of impaired T-cell homeostasis during cART. In particular, we aim to study the modifications of T-cell homeostasis, microbial translocation, gastrointestinal function and faecal microbiota composition in a cohort of HIV-infected, antiretroviral-naïve subjects prior to and following 12 months of cART (aim 1). A further goal is to investigate the contribution of Th17/Th22, “gut-homing” and Tscm cells in sustaining peripheral immune defects in HIV-infected, antiretroviral-naïve subjects prior to and following 12 months of cART (aim 2, immunological substudy).
In Aim 1 we consecutively enrolled 160 HIV-infected, antiretroviral-naïve subjects introducing cART (T0), and presenting virological suppression (<40 cp/mL) and active follow-up after 12 months of treatment (T12). We performed: i) flow cytometry surface staining (naïve, memory, activated CD4/CD8 T-cells); ii) microbial translocation parameters analysis (LPS, sCD14, EndocAb); iii) gastrointestinal functional marker assessment (LAC/MAN fractional ration, I-FABP); iv) faecal calprotectin quantification and microbial population analysis.
In Aim 2 we selected a subgroup of 28 HIV-infected, antiretroviral-naïve subjects introducing cART (T0) with available cryopreserved biological samples from the cohort of patients enrolled in Aim 1. 18 HIV-uninfected age- and sex-matched individuals were selected as controls. After lymphocyte separation, we performed flow Cytometry surface staining to assess CD4+ and CD8+ activation (HLA-DR+CD38+), maturation (naïve: CCR7+CD45RA+; central memory: CCR7+CD45RA-; effector memory: CCR7-CD45RA-; terminally differentiated: CCR7-CD45RA+) exhaustion (PD-1+), the frequency of stem cell-like memory T cells (Tscm; CCR7+CD45RA+CD27+CD95+) and that of CD4+ T-cells with a “gut homing” (CCR9+α4β7+) and a “Th17/Th22” phenotype (CCR6+CD161+).
Our Aim 1 results showed a significant increase in central memory (p<0.0001;) and naïve CD4+ T-cells (p<0.0001) which paralleled the reduction of activated (p=<0.0001) and memory activated T-cells (p<0.0001). No differences were observed in terms of naive and central memory CD8+ T-cells.
No changes were observed in microbial translocation parameters and intestinal permeability at T12, while we registered an increase in I-FABP (p=0.0002) and a decay in faecal calprotectin levels (p=0.0099) after introducing cART.
Qualitative analysis of the faecal microbiome revealed an outgrowth of Lactobacillus (p<0.0001) and Bacteroides spp. (p=0.0006) as well as Proteobacteria (p=0.027) following cART.
Regarding Aim 2, we registered a significant reduction of activated CD4+ (p=0.02) and CD8+ lymphocytes (p=0.0003) following cART introduction, reaching levels comparable to those observed in uninfected controls. Analysis of T-cell maturation showed a significant reduction in CD4+ effector memory subsets in the course of cART (p=0.01), leading to persistent impairment of this subset compared to controls.
Measure of PD-1 displayed a hierarchy in PD-1 expression, with the highest levels in cART-naïve subjects, followed by those measured in treated individuals and uninfected controls.
Study of Tscm revealed significant reduction of the CD4+ Tscm subset in HIV-infected subjects during the first 12 months of cART (p=0.002) and no variations of the CD8+ Tscm pool. Overall, HIV infection accounted for lower CD4+ and CD8+ Tscm frequencies compared to uninfected controls. Interestingly, Tscm correlated negatively with naïve cells (CD4+: r=-0.7; p=0.004; CD8+: r=-0.7; p=0.006) and positively with effector memory cells in healthy controls. (CD4+: r=0.6; p=0.01; CD8+; r=0.6; p=0.01). In HIV disease, these correlations were lost in the course untreated infection and only the relationship between CD4+ naïve and Tscm cells was restored in the course of cART.
Analysis of Th17/Th22 frequency showed enrichment in the course of cART (p=0.03;), but significantly lower frequencies compared to HIV-uninfected controls (p=0.04). Interestingly, this subset correlated positively with CD4+ Tscm prior to cART (r=0.6; p=0.002).
Finally, a progressive contraction of CD4+ T-cells with a “gut-homing phenotype was reported (p=0.02), which maintained significantly lower frequencies compared to HIV-uninfected controls (p=0.04). A positive correlation was found between T cells with a “gut-homing” phenotype and plasma HIV RNA prior to cART introduction (r=0.5; p=0.003). In line with this finding, this phenotype also correlated with activated CD4+ T-cells (r=0.5, p=0.003) at the same time-point; this association was nonetheless lost in the course suppressive treatment.
In conclusion our study demonstrated that 1 year of virally-successful cART results in an amelioration of peripheral T-cell homeostasis with reduction of T-cell activation and exhaustion parameters despite persistent microbial translocation and intestinal damage/permeability, possibly linked to the impairment of Th17/Th22 and cells with a “gut-homing” immunephenotype. Further research is necessary to investigate the effects of longer cART on circulating T-cell subpopulations and markers of gut homeostasis and function.
2
Aloufi, Nawaf. "The role of sCD127 in IL-7-Mediated T Cell Homeostasis in Vivo." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/41089.
Full textAbstract:
Interleukin-7 is an essential cytokine that plays a major role in the development and homeostatic maintenance of T-cells. The presence of soluble forms of various cytokine receptors have been proposed to be involved in the endogenous regulation of cytokine activity. Due to the natural ability of soluble CD127 (sCD127) to bind to IL-7, there is an interest in its potential application as an immunotherapeutic agent in diseases, where IL-7 has been found to be relevant, including HIV infection. In this study, I hypothesize that by administering sCD127 to healthy mice, IL-7 activity should be enhanced, thus enhancing T cell proliferation in vivo.
The work presented here focuses on three main objectives: 1) evaluating the effect of IL-7 with or without sCD127 on T cell proliferation in healthy mice; 2) validating a mouse model of T cell depletion using anti-CD4 and CD8 antibodies; and 3) determining the effect of sCD127 treatment with or without IL-7 on T cell reconstitution and proliferation in the T cell depletion model. To assess the effect of administering exogenous sCD127, IL-7 or the combination on T cell proliferation, peripheral blood mononuclear cells and spleen were isolated, and stained to characterize T cell number, proliferation, and surface CD127 expression by flow cytometry. For the T cell depletion model, wild type C57BL/6 mice were injected intra-peritoneally with 150 μg single dose of anti-CD4 and anti-CD8 depleting antibodies. Consequently, mice were bled weekly to demonstrate the kinetics of T cell reconstitution following depletion (from d7 to d63).
Our results demonstrated that in healthy mice daily treatment with murine IL-7 significantly stimulated T cell proliferation and consequently increased cell number. This observation was further boosted by pre-complexing IL-7 with sCD127. For T cell depletion experiments, the kinetics of T-cell reconstitution was different between the CD4+ and CD8+ T cells. CD4+ T cell reconstitution was almost complete 6 weeks following T cell depletion, while CD8+ T cells were only partially reconstituted at this time point. Treatment with IL-7 or combined therapy had a transient and significant effect on T cell proliferation and reconstitution, and this influence was abrogated after treatment discontinuation. Interestingly, CD8+ T cells exert greater responses to our treatments in that a more pronounced proliferation and significant increase in cell number was observed relative to the effect seen on CD4+ T cells in both healthy and depleted mice.
In conclusion, antibody-mediated T cell depletion is a potentially valuable tool to investigate lymphopenia-induced proliferation and potential therapies thereof. This study suggests that combining sCD127 and IL-7 therapies enhances IL-7-mediated T cell proliferation, and provides important information for the potential therapeutic use of sCD127 and its impact on IL-7 function.
3
Almeida, Afonso Rocha Martins de. "CD4+ T cell homeostasis : the thymus, the cells and the environment." Doctoral thesis, Porto : Edição do Autor, 2002. http://hdl.handle.net/10216/64644.
Full text
4
Almeida, Afonso Rocha Martins de. "CD4+ T cell homeostasis : the thymus, the cells and the environment." Tese, Porto : Edição do Autor, 2002. http://catalogo.up.pt/F?func=find-b&local_base=UPB01&find_code=SYS&request=000090183.
Full text
5
Goldrath, Ananda W. "T cell homeostasis : a role for specific peptide/MHC ligands in homeostasis driven proliferation of naive CD8⁺ T cells /." Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/8332.
Full text
6
Bains, I. K. "Mathematical modelling of T cell homeostasis." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/20159/.
Full textAbstract:
T cell homeostasis describes the process through which the immune system regulates cell survival, proliferation, differentiation and death to maintain T cell numbers and diversity in a range of different conditions. The aim of this thesis is to better understand how this process leads to the development of the naive CD4+ T cell compartment during childhood. Mathematical modelling is used in combination with experimental observations to estimate naive T cell kinetics over the lifetime of an individual. The analysis described here shows that post-thymic proliferation contributes more than double the number of cells entering the pool each day from the thymus. This ratio is preserved from birth to age 20 years; as the thymus involutes, the average time between naive T-cell divisions in the periphery lengthens with age and the naive population is maintained by improved naive cell survival. Thymic output is quantified from birth to age 60 years by combining models to interpret naive T cell TRECs and Ki67 expression data. Three distinct phases of thymic T cell output are identified: (i) increasing production from birth to age 1 year; (ii) steep decline to age 8 years; (iii) slow decline from age 8 years onwards. Finally, the role of inter-cellular variation in T cell residency times is explored. It is able to explain the persistence of PTK7+ naive CD4+ T cells in thymectomised individuals. Importantly, the model predicts the accumulation of veteran PTK7+ T cells in older individuals and suggests that the residual population in thymectomised individuals will also consist predominantly of veteran PTK7+ T cells. The model has implications for the use of PTK7 as a marker of recent thymic emigration and also naturally explains improved T cell survival in older individuals.
7
Raynor, Jana L. "Regulatory T Cell Homeostasis in Aging." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1416570329.
Full text
8
Sather, Blythe Duke. "CD4+ Foxp3+ regulatory T cell homing & homeostasis /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8343.
Full text
9
Aksoylar, Halil I. "A Critical Role for Gimap5 in CD4+ T Cell Homeostasis and Maintenance of Peripheral Immune Tolerance." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367937122.
Full text
10
Boucher, Louis-martin. "T-cell receptor associated signals that modulate lymphocyte homeostasis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0028/NQ49933.pdf.
Full text
11
Palmer, Megan Joan. "Cytokine signaling control of naïve CD8⁺ T-cell homeostasis." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/60786.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2010.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 191-209).
Mounting effective adaptive immune responses requires a large naive T-cell population with a wide diversity of target specificity. Naive CD8⁺ T-cells depend on T-Cell Receptor (TCR) and ye cytokine signals for their homeostatic survival and proliferation, but differences in sensitivity to these homeostatic signals among T-cell clones have been generally attributed to differences in TCR specificity. This thesis describes the novel identification and characterization of intrinsic heterogeneity in the TCR-independent abilities of CD8⁺ T-cells to respond to homeostatic ye cytokines, and survive in their absence. These differences were predictably marked by expression of CD5, a surrogate marker of TCR:spMHC binding avidity. In vitro, CD5I T-cells proliferate more robustly to saturating levels of the y, interleukin (IL) cytokines IL-7, IL-2 and IL-15, while CD5" cells have prolonged survival in the absence of dedicated homeostatic cues. IL-7 is the most critical cytokine for naive T-cell homeostasis, and a detailed analysis of IL-7 signaling revealed that IL-7 responsiveness is primarily determined by IL-7 receptor (IL-7R) expression, which is correlated with CD5 expression. While T-cells share common relationships between IL-7-induced signaling and responses, the signaling network encodes distinct signaling requirements for survival, proliferation and CD8a induction responses. As a result, all T-cells survive when treated with high doses of IL-7, but only cells with a critically high level of IL-7R expression can induce sufficient signaling to proliferate. IL-7 depletion also scales with IL-7R expression, and the 'overconsumption' of IL-7 by CD5hiIL-7Rh T-cells can compromise their prolonged survival. In vivo, lymphoreplete mice preserve the homeostatic diversity of CD5 expression by maintaining physiological IL-7 levels that promote neither preferential proliferation nor survival of CD5hiIL-7Rh' and CD5'"IL-7R'" T-cells. However, elevated IL-7 levels in lymphopenic mice or lymphoreplete mice administered with exogenous IL-7 yield preferential expansion of CD5hiIL-7Rh T-cell subsets, elevating the mean CD5 expression of the T-cell repertoire. This demonstration of functional intrinsic heterogeneities in IL-7R expression between CD8⁺ T-cells supports a previously under-appreciated role for IL-7 in maintaining not only the size but also the diversity of the T-cell repertoire. Furthermore, the exemplified potential for preferential expansion of more auto-reactive CD5"I T-cells subsets has important implications for the design of cytokine therapies.
by Megan Joan Palmer.
Ph.D.
12
Schim, Van Der Loeff I. C. D. "The role of Zap70 in naïve T cell homeostasis." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1419150/.
Full textAbstract:
TCR signalling is crucial to both T cell development and naive T cell homeostasis. Naïve T cell survival in the periphery is thought to depend on both cytokine signalling and constitutive TCR signalling. The nature of this TCR dependent survival signal remains controversial. The tyrosine kinase, Zap70, is essential for TCR signalling. The aim of this project is to investigate the role of Zap70 in the transduction of survival signals in naïve T cells. Using mice that conditionally express Zap70 by means of a tetracycline-inducible system, we found that Zap70 is absolutely required for the maintenance of naïve T cells in the periphery. Loss of Zap70 resulted in a dramatic and rapid reduction in mature naive CD8 T cells in the blood and peripheral organs consistent with a naïve T cell survival defect. This survival defect could not be accounted for by cell-intrinsic differences in IL-7Rα or Bcl-2 expression. Analysis of T cell survival in vitro revealed no differences in responses to IL-7 between F5 T cells with or without Zap70. Survival in vitro was found to be enhanced by the presence of CD1 1 c+ enriched splenocytes but not T or B cells. Survival of F5 T cells in these cultures was dependent on Zap70 expression and also required intact MEK signalling. In addition, we also tested the ability of previously described Zap70 mutants, Zap70 SKG and Zap70YYAA, to transduce homeostatic TCR survival signals in vivo. Both mutants were unable to support the development, survival or antigen-induced expansion of F5 T cells. Additionally, we found evidence that Zap70Y YAA had a dominant negative effect on T cell development and reconstitution in F5 TetZap70 mice. In conclusion, we find that Zap70 is essential for transmission of signals required for naive T cell survival and requires both full expression and functionality of Zap70.
13
Kabat, Agnieszka Martyna. "The role of autophagy in intestinal T cell homeostasis." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:c19d02d1-da2a-482e-8ba2-e2f88211a507.
Full textAbstract:
A polymorphism in the essential autophagy gene ATG16L1 is associated with susceptibility to inflammatory bowel disease. However, the role of autophagy in maintenance of intestinal immune homeostasis remains unclear. Using targeted deletion of Atg16l1 in T cells, we demonstrate critical requirement for autophagy in generation of appropriate adaptive immune cell responses within the mucosa. Selective deletion of Atg16l1 in T cells resulted in spontaneous intestinal inflammation, characterized by accumulation of Th2 cells and aberrant antibody responses towards dietary and microbiota antigens. Foxp3+ Treg cells were dependent on autophagy for their survival and function within the intestinal lamina propria, where they acted to limit Th2 cell accumulation. In addition, we demonstrate a novel role for autophagy in limiting Th2 cell survival in a cell-intrinsic manner. The distinct requirements for autophagy in the survival of different intestinal CD4+ T cell subsets reveals a novel role for autophagy in mucosal T cell homeostasis, with potential implications for understanding and treatment of chronic inflammatory disorders.
14
Huynh, Alexandria. "Mechanisms of regulatory T cell lineage homeostasis and stability." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467375.
Full textAbstract:
Defined by the transcription factor Foxp3, regulatory T cells (Tregs) are a lineage of CD4+ T lymphocytes critical for the maintenance of immune homeostasis and tolerance. A lack of functional Tregs in both mice and humans leads to a fatal systemic autoimmune disease, underscoring their importance as mediators of tolerance to self antigen. One notable distinction between conventional T cells (Tconv) and Tregs is their differential control of the phosphatidylinositol 3-kinase (PI3K) pathway: PTEN, the primary negative regulator of PI3K, is expressed at high levels constitutively in Tregs, preventing the downstream activation of PI3K targets. Regulation of signaling through PI3K has previously been described to play an important role in the maintenance of homeostasis in Tconv, but has not been well characterized in Tregs.
Here, we show that control of PI3K in Tregs is essential for the maintenance of in vivo lineage homeostasis and stability. Mice lacking expression of Pten specifically in Foxp3+ Tregs developed an autoimmune/lymphoproliferative disease characterized by excessive TH1 responses, B cell activation and renal failure. Diminished control of PI3K activity in Tregs led to reduced expression of the high-affinity interleukin-2 (IL-2) receptor subunit CD25 and accumulation of Foxp3+CD25- cells in vivo. The downregulation of CD25 expression on PTEN- deficient Tregs preceded the eventual loss of Foxp3 expression in these cells, representing the total destabilization of the Treg lineage and accumulation of “exFoxp3 cells” in vivo. Collectively, these data demonstrate that control of PI3K signaling by PTEN is critical to maintain in vivo Treg homeostasis, function and stability.Medical Sciences
15
Fukunaga, Akiko. "Altered Homeostasis of CD4+ Memory T cells in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Chronic Graft-versus-Host Disease Enhances T cell Differentiation and Exhausts Central Memory T Cell Pool." Kyoto University, 2008. http://hdl.handle.net/2433/124214.
Full text
16
Gozalo, Sara. "The Role of γс Cytokines in T Cell Development, T Cell Homeostasis and CD8+ T Cell Function: A Dissertation." eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/140.
Full textAbstract:
T lymphocytes are essential components of the immune system and as such are continually regulated by a variety of factors. Every step of their development, survival and function is tightly monitored to ensure their ability to recognize most foreign agents and mount adaptive immune responses during pathogenic infections, while remaining tolerant to self-antigens. Among the many factors that participate in the regulation of T cell development and function are the cytokines. Cytokines that signal through the common gamma (γс) chain and the Janus kinase 3 (Jak3) include IL-2, -4, -7, -9, -15, and -21 and have been implicated in the regulation of every stage in the life of a T cell. Therefore, it is not surprising that mutations in the γс chain or Jak3 lead to a SCID condition in humans and mice. Specifically, Jak3-deficient mice are characterized by a reduction in thymic cellularity and dysregulated T cell homeostasis. They have an expansion of memory-like CD4+ mature T cells and an almost complete absence of mature CD8+ T cells. By investigating the TCR repertoire of CD4+ T cells in the thymus and spleen of Jak3-/- mice, I deduced that the CD4+ T cell activation and expansion is TCR-specific and takes place in the periphery of the mice. After crossing Jak3-deficient mice to Bcl-2 transgenic mice I showed that the developmental block observed in Jak3-/- mice could not be rescued by the anti-apoptotic factor, despite the fact that its expression did increase, slightly, the total numbers of developing thymocytes. The enforced expression of Bcl-2 was also not sufficient to revert the dysregulation of T cell homeostasis in Jak3-/- mice. Finally, in order to further understand the role played by γс cytokines during T cell function, I investigated the ability of mature Jak3-/- CD8+ T cells to become activated and differentiate into effector cells in response to a viral infection. My results indicate that CD8+ T cells are activated and proliferate in response to a viral infection, but their survival, as well as their ability to proliferate and differentiate into effector cells are greatly impaired, resulting in the inability of Jak3-deficient mice to mount a protective response.
17
Cho, Hyoung-Soo. "The Tec kinase ITK is required for homeostasis and anti-viral immune protection in the intestine." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/998.
Full textAbstract:
The Tec kinase ITK is activated by TCR stimulation and also required for TCR downstream signaling. Previous studies have reported differential roles of ITK and another Tec family kinase RLK in CD4+ TH differentiation and effector function. However, these findings are confounded by the complex T cell developmental defects in Itk-/- mice. Furthermore, the function of ITK in tissue-resident T cells in the intestine and anti-viral immune response to a persistent infection has not been studied previously. In addition to T cells, recent studies have indicated an expression of ITK in ILC2, but not in other ILC subsets. Yet, the role of ITK in ILC2 has not been characterized. Here, I have examined the role of ITK and RLK in CD4+ TH subsets using a small molecule inhibitor PRN694. I found that PRN694 impaired TH1 differentiation in vitro, and PRN694 administration prevented TH1-mediated colitis progression in vivo. In an MHV68 infection model, Itk-/- mice failed to control viral replication in the intestine, while gut-homing of CD8+ T cells was greatly impaired. Finally, I found that ILC2 number was markedly reduced in the intestine of Itk-/- mice. Gut-specific defect of Itk-/- ILC2 is associated with a low availability of IL-2 in the intestine of Itk-/- mice. Collectively, these data suggest that ITK is important in T cell migration to the intestine and ILC2 homeostasis in the intestine, thereby contributing to the protective response to a latent virus and intestinal tissue homeostasis.
18
Kashyap, Mohit. "Regulation of Murine Mast Cell Homeostasis by TGF-β1 and CD4+CD25+C Regulatory T Cells." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/950.
Full textAbstract:
Understanding mast cell development is central to allergic disease pathophysiology. Our laboratory has previously shown that cytokines such as IL-4 and IL-10 inhibit mast cell development from bone marrow progenitors. These studies encouraged our interest in other regulatory cytokines, including transforming growth factor β1 (TGF- β1). TGF- β1 has many cellular sources, one of which is CD4+CD25 regulatory T cells (Tregs). We wanted to determine the effects of Transforming Growth Factor (TGF) βl on mast cell development. We find that TGFβl decreased FcεRI, c-Kit, T1/ST2 and FcεR expression, and inhibited granule formation in developing mast cells. Accessory cells were not required for this inhibition. Smad3-deficiency did not alter the response of bone marrow cells to TGFβ1. TGFβl inhibited expression of the FcεRI a subunit protein, without decreasing β or γ proteins. Mast cells derived in the presence of TGFβl were functionally impaired, as IgE-mediated cytokine secretion was greatly reduced. The changes in granule formation and surface antigen expression were long-standing, as they were not reversed by transfer to W/WV mice. The TGF-β1 dependent transcriptional regulation of bone marrow cells from which mast cells develop was examined through DNA microarray analysis. Wild type (WT) bone marrow cells were stimulated with IL-3+SCF+vehicle or IL-3+SCF+TGF-βI for 10 days and their transcriptomes* analyzed. The results identified which components of transcriptional regulation were regulated by TGF- β1. Of particular interest was the upregulation of the β subunit of the FcεRI, inspite of no receptor surface expression and the differential regulation of various mast cell proteases (MCPs). This initial survey provides a potential starting point for further analysis of the role of TGF-β1 -dependent signaling in developing mast cells. Because they produce TGF-β1 and/or IL-10, regulatory T cell-dependent murine mast cell inhibition was examined. Co-culture of mast cells with regulatory T cells for 6 days downregulated mast cell number, high affinity IgE receptor and c-Kit surface expression. This led to a decrease in TNFa release making mast cells functionally impaired. By using Tregs from IL-10 KO mice, this effect was proven to be IL-10 dependent. Mast cells are mediators of inflammatory disease. TGFβl and IL-10 may contribute to mast cell homeostasis by inhibiting maturation from bone marrow precursors. The effects of TGFβ1 and regulatory T cell derived IL-10 result in greatly diminished expression of cell surface markers, reduced granulation, and lack of responsiveness to IgE-mediated activation. Thus TGFβl and/or CD+CD25+ T cells can serve as potent and multifunctional regulators of mast cell maturation and/or function.* A set of genes that are expressed in a cell at any given time.
19
Adelmann, Krista. "Regulatory T celle in skin homeostasis and inflammation." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:e0be4411-2ba4-480c-9dcb-b1648f1f3c13.
Full textAbstract:
Regulatory T cells (Tregs) are crucial controllers of inflammation. Patients with a genetic defect in the lineage defining transcription factor Foxp3 suffer from a broad spectrum of autoimmune diseases, including early manifestation of various types of skin inflammation. However, our knowledge about the properties of skin resident regulatory T cells under homeostatic and pathologic conditions and in particular in inflammatory diseases of the skin such as psoriasis is limited. In order to address this open question, phenotypic characterization and transcriptomic analyses of murine skin Tregs were performed. The majority of CD4+ T cells in homeostatic skin express the transcription factor Foxp3. These Tregs show a unique profile, are mainly thymic derived nTregs and are enriched in markers associated with a highly suppressive phenotype such as CD25, CD103, IL-10, ST2, and GATA-3. To delineate the role of Tregs in psoriasis-like inflammation, the imiquimod model of psoriasiform inflammation was used. Tregs are significantly increased during skin inflammation and retain their suppressive phenotype and trancriptome. Treg depletion before and during imiquimod treatment led to exacerbated inflammation and dense leukocytic infiltrate in the dermis and epidermis. Furthermore, the exacerbated inflammation was characterized by a significant increase in IL-12 and infiltration of IFN-γ and TNF-a producing, T-bet+ CD8+ and CD4+ T cells. IL-23 and IL-17 secreting dermal γδ T cells are pathogenic in the imiquimod model, but their cell numbers decreased in the absence of Tregs. Functional experiments demonstrated that myeloid-derived type I Interferon drove the exacerbated inflammation, which was dependent on CD4+ and CD8+ T cells. In conclusion, skin Tregs have a protective role in psoriasis-like inflammation and depletion of Tregs causes disease exacerbation and triggers an altered cytokine profile and cellular infiltrate. These findings assist in our understanding of tissue resident Tregs and how they maintain homeostasis and prevent inflammation in the skin.
20
Zeidan, Joumana. "Novel findings on the impact of HIV infection: Interplay between T cell development and peripheral T cell homeostasis." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104565.
Full textAbstract:
A hallmark of HIV infection is the gradual decline in CD4 T cells leading to AIDS and failure of the immune system. Depletion of CD4 T cells has been attributed to direct viral cytopathogenicity and hyperimmune activation which all lead to accelerated apoptosis. More recently, impaired thymic function has been shown to contribute to the numerical decline of CD4 T cells. The thymus is the primary source of de novo T cells that bear a broadly diverse T cell receptor (TCR) repertoire. In adults, the thymus produces every day approximately 50 million new T cells termed recent thymic emigrants (RTEs). Following their exit from the thymus, RTEs join the naive T cell compartment and upon antigen encounter differentiate into effector and memory T cells.Abstract
21
Ogura(Kato), Aiko. "CXCR3high CD8+ T cells with naive phenotype and high capacity for IFN-γproduction are generated during homeostatic T-cell proliferation." Kyoto University, 2019. http://hdl.handle.net/2433/242369.
Full text
22
Patterson, Andrew R. "Gimap5: A Critical Regulator of CD4+ T Cell Homeostasis, Activation, and Pathogenicity." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1544098387129747.
Full text
23
Jain, Nitya. "Multifaceted Regulation of Peripheral T Cell Tolerance and Autoimmunity by FOXP3+ T Regulatory Cells: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/416.
Full textAbstract:
Adaptive immunity requires T cell responses to foreign pathogens to be counterbalanced with the need to limit collateral destruction of the host’s own tissues. Further, the presence of a substantial pool of lymphocytes capable of recognizing selfantigen in the periphery poses a threat to the maintenance of peripheral tolerance and prevention of autoimmunity. Regulatory T cells (Treg) that can suppress potentially self-reactive T cells are critical regulators of peripheral tolerance as well as initiation of immune responses. Treg cells employ several context-dependent mechanisms to establish regulation. In this thesis, we describe two distinct pathways of regulation used by Treg cells involving negative costimulation by CTLA-4 and immunomodulation by the morphogen, TGFβ.
CTLA-4 is a co-inhibitory receptor on T cells essential for maintaining T cell homeostasis and tolerance to self. CTLA-4 expression is induced in conventional T cells following activation, whereas it is constitutively expressed in regulatory FOXP3+CD4+ regulatory T cells. Mice lacking CTLA-4 develop an early onset, fatal breakdown in T cell tolerance. Whether this autoimmune disease occurs because of the loss of CTLA-4 function in regulatory T cells, conventional T cells, or both, is not known. We present evidence here that in addition to a critical CTLA-4 function in regulatory T cells, CTLA-4 in conventional T cells is also necessary for controlling the consequences of abnormal T cell activation. CTLA-4 expression in activated conventional T cells only in vivois unable to compensate for the impaired function of CTLA-4-less regulatory T cells that results in systemic lymphoproliferation, but it can prevent the aberrantly activated T cells from infiltrating and fatally damaging non-lymphoid tissues. These results demonstrate that CTLA-4 has a dual function in maintaining T cell homeostasis: CTLA-4 in regulatory T cells inhibits inappropriate naïve T cell activation and CTLA-4 in conventional T cells can prevent the harmful accumulation of inappropriately activated pathogenic T cells in vital organs.
In addition, we have identified Disabled-2 (Dab2), a TGFβ signaling intermediate, as a FOXP3 target gene that is expressed exclusively in Treg cells and is critical for in vitro and in vivo regulation by Treg cells. During T cell development, DAB2 is also expressed in a Foxp3-independent manner in thymic precursor cells, and acts as a sensor of TGFβ signals that is required for programming normal TGFβ responsiveness in T cell progenies. Naïve CD4+ T cells that differentiate from Dab2-deficient precursors favor Th17 cell generation at the expense of FOXP3+ Treg cells as a result of altered sensitivity to TGFβ. Importantly, retinoic acid can restore TGFβ signaling capacity of naïve CD4+ T cells generated from Dab2-deficient precursors, emphasizing the cooperative nature of retinoic acid and TGFβ signaling pathways in promoting Treg cell development and maintenance.
24
Veerman, Krystle. "The role of PSGL-1 in T cell migration and homeostasis." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/36927.
Full textAbstract:
P-Selectin Glycoprotein Ligand-1 (PSGL-1) is an extracellular glycoprotein expressed on most leukocytes that is important for rolling and tethering of activated leukocytes to areas of inflammation through direct interactions with P-selectin, E-selectin and L-selectin. However, PSGL-1null mice showed subtle defects in their homeostatic T cell profile that cannot be adequately explained by a defect in migration of activated leukocytes. PSGL-1null mice had a reduced number of CD4+ and CD8+ T cells in the peripheral blood but not in the lymph nodes and spleen. T cell subset analysis revealed that there was a severe reduction of naïve T cells in the peripheral blood and a moderate reduction of naïve T cells in the lymph nodes whereas other T cell compartments were not as affected. Here we determined that PSGL-1 was important for the homing of T cells to secondary lymphoid organs and that PSGL-1 functioned independently of selectin interaction. PSGL-1 enhanced T cell homing through an interaction with secondary lymphoid chemokines CCL21 and CCL19. We have also shown that PSGL-1null T cells are delayed in leaving the lymph nodes suggesting PSGL-1 is important in the movement of T cells both in and out of lymph nodes. Therefore, the reduced ability of PSGL-1null T cells to enter lymph nodes and receive survival factors may contribute to disturbed T cell subsets in peripheral blood and lymph nodes of PSGL-1null mice.
There is evidence of spontaneous CD8+ T cell specific proliferation in PSGL-1null cells in lymphoreplete environments. This appears to be caused by a combination of factors, namely an increase in lymph node residence time as well as a more rapid proliferative response to the homeostatic cytokines IL-15, IL-2 and IL-4. However, PSGL-1null T cells are also less viable both in vivo and in vitro. Therefore, spontaneous proliferation may be a compensatory mechanism that balances T cell levels to normal in lymph nodes and spleens of PSGL-1null mice. These findings collectively demonstrate a novel, selectin-independent role for PSGL-1 on T cells under non-inflammatory conditions both in T cell homing to secondary lymphoid organs as well as maintenance of T cell homeostasis.
25
Bonaguro, Lorenzo [Verfasser]. "Creld1 controls T cell homeostasis in mouse and human / Lorenzo Bonaguro." Bonn : Universitäts- und Landesbibliothek Bonn, 2020. http://d-nb.info/1238729010/34.
Full text
26
Li, Ou. "CD24 in T lymphocyte homeostatic proliferation and autoimmune disease." Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1124255377.
Full textAbstract:
Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xiv, 131 p.; also includes graphics (some col.). Includes bibliographical references (p. 122-131). Available online via OhioLINK's ETD Center
27
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.
Full text
28
Renkema, Kristin. "Differential Maintenance, Function, and Transcriptional Profile of CD8⁺ T cells with Age." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/293484.
Full textAbstract:
Infectious diseases remain amongst leading causes of death in people aged 65 years and older; therefore, much research is focused on determining the immune components that contribute to age-dependent increased susceptibility to, and increased mortality from, infections. CD8⁺ T cells are critical for clearing intracellular pathogens through production of cytokines and direct killing of infected cells. Age-dependent CD8⁺ T cell alterations have been described, including decreased numbers of naïve CD8⁺ T cell precursors and decreased numbers and function during infection. This dissertation explores the mechanisms contributing to these changes. First, we demonstrated that multiple mechanisms contribute to changes in the CD8⁺ T cell pool with age. CD8⁺ T cells from unimmunized T cell receptor transgenic (TCRTg) old mice undergo massive virtual memory (VM) conversion with age; both homeostatic proliferation and cross-reactivity may contribute to the generation and accumulation of VM cells with age. These VM cells exhibit an age-dependent replicative impairment to cognate antigen, which points to possible detrimental functional consequences due to changes in the overall T cell pool. Second, we evaluated the cell intrinsic contribution to the decreased old CD8⁺ T cell response. With in vitro stimulation, old CD8⁺ T cells exhibit decreased ability to enter into late cell divisions and decreased production of effector molecules. In addition, we found that old CD8⁺ T cells have decreased expression of the master transcription factor T-bet, which correlates to decreased effector function and terminal differentiation in vivo. Collectively, these results identify possible cell-intrinsic targets for improving CD8⁺ T cell immunity. Finally, we measured whether a Listera monocytogenes live vaccine model induces protective immune responses in old mice. We found that vaccination conferred little protection in old mice upon pathogen challenge. These results contrast with other vaccine models, which may allow for pinpointing both the vaccine and immune components required for generating strong protective immunity in the elderly. Collectively, this dissertation demonstrates that CD8⁺ T cell precursors, effector cells, and memory cells exhibit profound changes with, age and identifies both possible mechanisms contributing to these alterations as well as possible therapeutic/vaccine targets for improving immunity in the elderly.
29
Mahammad, Saleemulla. "Cholesterol in T cells homeostasis, plasma membrane organization and signaling /." Doctoral thesis, Stockholm : The Wenner-Gren Institute, Stockholm University, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-38357.
Full textAbstract:
Diss. (sammanfattning) Stockholm : Stockholms universitet, 2010.At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: In press.
30
Hackenbroch, Jessica. "CD4⁺ and CD8⁺ naïve T-cell homeostasis in primary progressive multiple sclerosis." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112629.
Full textAbstract:
Multiple Sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system. The etiology of MS is unknown but many researchers believe that it is autoimmune mediated. This study investigated naive CD4+ and naive CD8+ T-cell homeostasis in patients with Primary Progressive Multiple Sclerosis and Relapsing Remitting Multiple Sclerosis. The naive T-cell compartment involves a balance between thymic production of naive T-cells, homeostatic proliferation and the delivery of death and survival signals. Naive T-cell production was quantified by measuring signal joint T-cell receptor excision circles (sj-TRECs); episomal byproducts formed during V(D)J T-cell receptor rearrangement.Homeostatic proliferation was quantified by flow cytometry analysis of % expression of CD31 and Ki-67. CD31 is a marker found on CD4+ recent thymic emigrants (RTE) but not on naive T-cells that have undergone homeostatic proliferation. CD31 can be used as a marker of the proliferation history of naive CD4+ T-cells. Ki-67 is a nuclear and nucleolar antigen found in actively cycling cells. It can be used as a marker of cell proliferation at the moment of isolation. Cell survival was measured by quantifying plasma IL-7 levels and by measuring Bcl-2 expressions. IL-7 plays an important role in maintaining and restoring peripheral naive T-cell homeostasis. It stimulates naive T-cell proliferation and prevents the reduction of Bcl-2, an antiapoptotic protein.
In this study, PPMS patients had significantly reduced naive CD4 + T-cell sj-TRECs compared to healthy controls (p = 0.0007) and compared to RRMS patients (p = 0.0010). RRMS patients had fewer sj-TRECs than healthy controls but this difference was not significant (p = 0.4652). Similarly, in PPMS, naive CD4+ T-cells had significantly lower CD31 expression than healthy controls (p = 0.0017) and RRMS patients (p = 0.0032). This finding indicates increased homeostatic proliferation in naive CD4 + T-cells in PPMS, most probably a response to decreased thymic export as marked by the decreased naive CD4+ T-cell sj-TRECs. % CD31 expression in naive CD4+ T-cells did not differ significantly in RRMS compared to healthy controls (p = 0.7455) which is consistent with their naive CD4+ sj-TREC levels.
Naive CD8+ T-cell sj-TRECs were significantly reduced in PPMS patients compared to healthy controls (p = 0.0212) but not compared to RRMS patients (p = 0.2379). RRMS patients had fewer naive CD8 + T-cell sj-TRECs compared to healthy controls but this difference was not significant (p = 0.1517). PPMS patients expressed increased Bcl-2 levels in their naive CD8+ T-cells. This finding indicates upregulation of survival signals, most probably a consequence of reduced thymic export of naive CD8+ T-cells.
The data from this study indicate that PPMS is different from RRMS in their naive CD4+ T-cell sj-TRECs and naive CD4 + T-cell % CD31 expression but is similar to RRMS in their naive CD8+ T-cell sj-TRECs. This study concludes, therefore, that both PPMS and RRMS patients have altered naive T-cell homeostasis.
31
Majri, Sonia. "Regulation of CD4⁺ memory T cell homeostasis by STAT5 during TCR restimulation." Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC139.
Full textAbstract:
Les facteurs de transcriptions Signal Transducer and Activator Transcription (STAT) sont essentiels pour la régulation de gènes impliqués dans plusieurs fonctions biologiques, y compris la réponse immunitaire. Nous avons étudié un patient ayant une nouvelle mutation ponctuelle hétérozygote dans le gène STAT5B. Les symptômes cliniques majeurs observés chez ce patient sont thrombocytopénie immune (TPI), lymphadenopathies, concentration élevée en anticorps IgM dans le sérum et hypergammaglobulinémie. Nous avons observé une accumulation anormale de lymphocytes T mémoires effecteurs (LME). Une analyse du transcriptome du patient a permis d'observer une sous-expression des gènes régulés par STAT5. De plus, nous avons révélé que les LME du patient étaient résistants à la mort induite par la restimulation du TCR. Ces résultats démontrent un rôle important et inattendu de STAT5 dans la régulation de l'homéostasie des lymphocytes T mémoires pendant la restimulation du TCRSignal transducer and activator transcription (STAT) proteins are essential transcription factors regulating gene expression involved in many biological functions especially immune responses. Here we report a patient with a de novo heterozygous missense mutation in STAT5B gene resulting in altered STAT5 transcriptional function. The patient presented with immune thrombocytopenia, lymphadenopathy, splenomegaly, an antibody class switching defect and granulocytosis with necrotizing granulomas. We found a specific dysregulation of CD4+ T cell subsets with an abnormal accumulation of effector memory T (TEM) cells. Transcriptome analysis in patient's T cells revealed a selective downregulation of the STAT5-dependent IL-2 signaling pathway. We found that TEM cells from the patient were resistant to in vitro TCR restimulation-induced cell death. These results demonstrate a key role of STAT5 in memory T cell homeostasis by regulating cell death during TCR restimulation
32
Saini, Manoj. "The role of TCR and cytokine signals in naïve T cell homeostasis." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1446076/.
Full textAbstract:
The peripheral T cell compartment is maintained at a constant size, resulting from a balance of cell development, survival, proliferation and death. Transmission of signals through the TCR and IL-7R on the T cell surface is involved in regulating all these processes, however the precise manner in which these signals together maintain T cell homeostasis is unclear. To investigate the contribution of TCR and IL-7 signals to naive T cell homeostatic responses we established two model systems. To specifically address the role of homeostatic TCR signalling in the development and maintenance of the T cell compartment, we generated transgenic mice that conditionally express the Syk family tyrosine kinase Zap70. The transduction of TCR signals by Zap70 is essential for thymic development and T cell activation. Given the importance of Zap70 expression in T cell antigen receptor signalling, we investigated whether Zap70 was also essential for the transmission of TCR signals, required for the steady state survival of the peripheral naive T cell compartments. Zap70 deficient mice exhibit a complete block in thymopoiesis at the DP stage in the thymus and as a consequence lack mature peripheral T cells. For this reason we generated mice that express Zap70 in a conditional manner, using the tetracycline responsive gene regulatory system. Thymic selection proceeded normally in these mice, however ablation of Zap70 expression resulted in the disappearance in the peripheral naive CD4+ and CD8+ T cells, with the naive CD8+ T cell compartment appearing most affected by the loss of Zap70 expression. This data suggests an important role for Zap70 signalling in the transmission of homeostatic TCR survival signals. Unexpectedly we also found that TCR signals transmitted by Zap70 had the capacity to influence IL-7R expression and importantly revealed a novel role for positive selection signals in the regulation of peripheral IL-7R expression and therefore the competitive fitness of peripheral T cell clones. The second model system examined the homeostatic responses of class I MHC restricted F5+/+ TCR transgenic Rag1A CD8+ T cells following transfer into MHC class I or IL-7 deficient hosts, to specifically quantify the contribution of TCR and IL-7 signals in naive T cell homeostasis. Our data reveals that IL-7 signals are more essential than homeostatic TCR signals for the survival of the naive T cell compartment in conditions of lymphopenia. Interestingly we also demonstrate that IL-7 may exert part of its homeostatic effects by modulating TCR engagement with MHC ligands by regulating T cell - APC interactions in vivo. In conclusion the data presented in this thesis confirms that TCR and IL-7 signals are essential for naive T cell homeostasis, but also reveals extensive cross-talk between homeostatic TCR and IL7 signals in the control of peripheral T cell homeostasis.
33
Wang, Chunjing. "Role of CTLA-4 in CD4 T cell homeostasis, function and differentiation." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10046608/.
Full textAbstract:
CTLA-4, as a member of CD28 receptor family, has been widely accepted as an important negative regulator of immune responses and plays an essential role in maintaining self-tolerance. Accordingly congenital ablation of the CTLA-4 gene in mice causes uncontrolled lymphoproliferation and extensive autoimmune tissue destruction. Here we demonstrate that CTLA-4 deficiency not only results in hyperactivated conventional T cells, but also causes an increased regulatory T cell (Treg) compartment, which can be largely attributed to enhanced proliferation of Treg in the periphery. Through short-term anti-CTLA-4 antibody treatment of wildtype and CD28-deficient mice, we reveal CTLA-4-mediated control of Treg proliferation is dependent on control of CD28 signaling. In addition to regulating Treg proliferation, data from an adoptive transfer model of type 1 diabetes suggests CTLA-4 is an important component of Treg suppression in vivo. For years, CTLA-4 was thought to function extrinsically in Treg but intrinsically in conventional T cells. In this project, we show CTLA-4 expressed on conventional T cells can also work in a cell extrinsic manner. In this way, antigen-specific-CTLA-4-sufficient conventional T cells can restrain the proliferative responses of CTLA-4-deficient ones upon co-transfer. However CTLA-4-sufficient conventional T cells cannot replace Treg for the maintenance of peripheral tolerance. Accordingly, CTLA-4-sufficient conventional T cells only partially control lymphoproliferative disease induced by CTLA-4-/- bone marrow cells whereas its-sufficient Treg completely prevent disease in this setting. In addition, we demonstrate that the CTLA-4/CD28 pathway also plays a key role in controlling follicular helper T cell differentiation and subsequently germinal center B cell development. Taken together, our data in this study yield new insights into how the CTLA-4 pathway controls immune responses in vivo.
34
Johnson, Jenny Lynn. "Bacterial Exposure and Immune Homeostasis: A Mechanistic View of the Hygiene Hypothesis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1427988771.
Full text
35
Arojo, Omotooke Ajoke. "The Role of Sin 1-mTORC2 in the Regulation of T Cell Homeostasis." Thesis, Yale University, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10783434.
Full textAbstract:
In healthy individuals, T cells generally exist in a state of equilibrium or homeostasis. This homeostasis is achieved by a tight and dynamic regulation of signaling cascades that control T cell numbers, localization, metabolism, and differentiation at any given time. Dysregulation of T cell homeostasis underlies several immunopathologic conditions including autoimmune diseases and cancer, hence the need to better understand molecular mechanisms that control T cell homeostasis. The mechanistic target of rapamycin (mTOR) is a critical hub within several important signaling cascades that are operational throughout the life of a T cell from thymic development to antigen encounter and beyond. While significant progress has been made in uncovering the roles of mTOR in various aspects of T cell immunity, the molecular mechanisms that dynamically regulate the threshold of mTOR signaling at various stages of the T cell life cycle and how this contributes to T cell homeostasis are poorly understood. mTOR functions as the enzymatic nucleus of two multiprotein complexes designated mTOR complex 1 (mTORC1) and mTORC2. We investigated the role of mTORC2 in naïve T cell homeostasis and the dynamic biochemical regulation of mTORC2 signaling by Sin1 and its isoforms. This led us to uncover a previously unappreciated but fundamental aspect of T cell biology; active mTORC2 signaling in naïve T cells suppresses bone marrow homing and in this manner allows T cells recirculate more efficiently through secondary lymphoid organs for better immune-surveillance. Furthermore, our exploration of the dynamic biochemical regulation of mTORC2 in naïve versus activated T cells revealed a potential mechanism through which dynamic mTORC2 signaling is achieved. We found that the overall strength of mTOR signaling is controlled at the level of transcriptional expression of mTOR and its adaptors by TCR stimulation. More broadly, we also investigated the biochemical regulation of mTORC2 by Sin1 isoforms, taking advantage of their domains to understand how various upstream signals might control mTORC2 activity. Through these investigations, we established that Sin1 isoforms differentially regulate mTORC2 response to Pi3K and non-Pi3K signals as well as mTORC2 target substrate specificity.
36
Fitz-Gerald, Leslie. "Naive CD4+ T-cell homeostasis in primary progressive and secondary progressive multiple sclerosis." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106368.
Full textAbstract:
The peripheral naive CD4+ T-cell pool is maintained through homeostatic mechanisms, which balance thymic output, cell survival and death, and peripheral T-cell proliferative processes. Naive CD4+ T-cells are divisible into several subsets based on their surface expression of CD31: cells having highest levels of expression of CD31 correspond to recent thymic emigrants (CD4+ RTEs), whereas CD31-negative (CD31neg) naive CD4+ T-cells have lost CD31 expression and are distant in origin from the thymus. We report that SPMS patients have altered naive CD4+ T-cell homeostasis with increased TCR-signalling and loss of CD31 from naive CD4+ T-cells with increasing age. Second, we report increased proliferation of the CD31neg subset of naive CD4+ T-cells in both SPMS and PPMS compared to controls. PPMS patients had an increased frequency of CD31neg naive CD4+ T-cells expressing the Fas receptor CD95. We conclude in PPMS that CD31neg cells have an increased propensity for cell death following proliferation. Self-peptide-MHC induced TCR signalling helps maintain naive CD4+ T-cell survival. TCR signalling with loss of CD31 leads to loss of the immunoregulatory function of CD31 molecules in naive CD4+ T-cells, i.e. would favour the development of autoimmune processes. Furthermore, increased proliferation of CD31neg naive CD4+ T-cells is known to expand auto-reactive T-cells, i.e. may contribute to ongoing autoimmune processes in progressive MS. In conclusion, we report peripheral naive CD4+ T-cell homeostatic alterations in both SPMS and PPMS that have potential implications for ongoing immunopathogenesis of these MS subtypes.La population des cellules-T CD4+ naïves périphériques est maintenue par des mécanismes homéostatiques qui fonctionnent en balancent la sortie du thymus, la survie et la mort des cellules, et la prolifération périphériques des cellules-T. Les cellules-T naive CD4+ se divisent en plusieurs sous-ensembles en fonction de leur expression de CD31 en surface: Les cellules ayant un plus haut niveau d'expression de CD31 correspondent aux émigrants thymiques récents (CD4+ ETRs), alors que les cellules CD31-négatif (CD31neg) ont perdu l'expression de CD31 et sont éloignées de l'origine du thymus. Nous avons constaté que chez les patients atteints de SPPS, l`homéostasie des lymphocytes-T CD4+ naïves est alterée, et se caractérise par une augmentation de la signalisation des récepteurs des cellules-T (RCT) et par la perte de CD31 des cellules-T CD4 + naïves avec l'âge. Deuxièmement, nous avons constaté une augmentation de la prolifération du sous-ensemble CD31neg des cellules-T CD4+ naïves chez les patients atteints de SPPS et SPPP comparé aux controles. Les patients atteints de SPPP avaient une fréquence accrue dede type CD31neg exprimant le récepteur Fas, CD95. Nous concluons que les cellules CD31neg des patients atteints de SPPP ont une propension accrue à la mort cellulaire après leur prolifération. La signalisation des TCR induite par le complexe auto-peptide-CMH-induit signalisation des TCR permet de maintenir la survie des cellules-T CD4+ naives. Le signalisation des TCR avec un perte de CD31 entraîne la perte des fonctions immunorégulatrices des molécules CD31 dans les cellules-T CD4+ naives ; i.e. favorisant le développement de processus auto-immunitaires. En outre, la prolifération des cellules-T CD4 + naïves de type CD31neg est une cause connue de l'augmentation des cellules-T auto-réactives, c'est-à-dire peuvent contribuer à l'établissement de processus auto-immunitaires dans la SP progressive. En conclusion, nous rapportons des modifications homéostatique périphériques des lymphocytes-T CD4 + naïves dans les deux SPPS et PPPS ayant des implications potentielles pour l'immunopathogènes de ces sous-types de SP.
37
Agrawal, T. "Epithelial ErbB2 regulation of thymus homeostasis and age-associated T cell mediated immunity." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10048131/.
Full textAbstract:
The molecular mechanisms governing the functional and structural decline of thymus with age, causing thymic immunosenescence, are incompletely identified. Using a bitransgenic mouse model, Dr Giangreco discovered that the over-expression of receptor tyrosine kinase ErbB2 causes reversible thymic atrophy. The over-expression of epithelial ErbB2 upon doxycycline administration in bitransgenic mice led to decreased thymus size and cellularity, loss of cortical-medullary boundary and abnormal T cell differentiation, bearing similarity to age-dependent thymic involution. This thesis set out to investigate this observation in more detail. I demonstrated that the observed atrophy in bitransgenic thymuses was because of thymus-specific ErbB2 expression, by employing foetal thymic organ cultures. In addition, I showed that over-expression of epithelial ErbB2 disrupted the thymic epithelial cells distribution. Also, an increase in Sca1+Cd49f+ epithelial cells with stem cell potential was noted, explaining why the thymic atrophy in bitransgenic mice was reversible. Exploration of the potential mechanistic pathways found that the thymic atrophy phenotype of K14-NICDER mice, in which epithelial Notch is activated upon tamoxifen administration, resembled the bitransgenic mouse thymic atrophy phenotype. However, mechanistic studies failed to establish ErbB2 acting upstream of Notch, and require further investigation. Administration of Lapatinib, an ErbB2 inhibitor improved the thymic organization and function in aged mice. Lapatinib treatment of aged mice also enhanced vaccine responses to Prevenar 13, a Streptococcus pneumoniae glycoconjugate vaccine, and increased the efficacy of vaccination to protect against subsequent pneumonia challenge. However my results showed that ErbB2 inhibition does not reverse thymic atrophy in scurfy mice, which have truncated Foxp3 protein, and an autoimmune phenotype. In conclusion, this study highlights the importance of ErbB2 in maintaining thymus homeostasis and thymus mediated immunity, and proposes a novel ErbB2 inhibition therapy for rejuvenating an aged thymus, to counter the associated immunosenescence and thereby improve vaccine responses.
38
Matsuda, Jennifer L. "Development, homeostasis and function of CD1d-restricted natural killer T cells /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2002. http://wwwlib.umi.com/cr/ucsd/fullcit?p3044780.
Full text
39
Ekholm, Pettersson Frida. "T-cell Differentiation and Immunological Homeostasis in Lymphopenic and Kappa Light Chain Deficient Mice." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5290-6/.
Full text
40
Schmidt, Emily Marta. "Role of the CTLA-4 receptor in regulatory T cell development, homeostasis and function." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1291/.
Full textAbstract:
Autoimmunity can occur when self-reactive lymphocytes of the adaptive immune system are activated upon encounter with antigen. This can lead to the development of debilitating and potentially life-threatening autoimmune diseases such as type-1 diabetes, rheumatoid arthritis and multiple sclerosis. Regulatory T cells (Tregs) are a subset of CD4+ T cells that express the lineage-specific transcription factor Foxp3 and exert dominant peripheral tolerance to maintain immune homeostasis. It is therefore important to fully understand the underlying mechanisms of Treg development, homeostasis and function due to the positive and negative effects that therapeutic manipulation could have on this essential T lymphocyte population. Many effector molecules have been proposed to have a central role in regulatory T cell function, and it is now clear that Tregs are equipped with multiple mechanisms by which to exert suppressive function. It has been reported that the cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor is constitutively expressed by regulatory T cells and a role for this molecule in Treg suppression has been suggested. This investigation revealed a role for CTLA-4 in maintaining homeostasis of the peripheral regulatory T cell compartment. In addition, using a transgenic mouse model that permitted the development of antigen-specific Ctla-4-deficient Tregs, a role for the CTLA-4 receptor in Treg suppressive function was identified. The data obtained suggest that the CTLA-4 receptor may function on regulatory T cells by modulating CD80/CD86 co-stimulatory molecule expression by antigen-presenting cells, and hence their capacity to activate conventional T cells to generate effector T cells and instigate an effective immune response.
41
Fields, Maria. "Homeostasis and function of Regulatory T Cells during Human Immunodeficiency Virus infection." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1408709850.
Full text
42
Zhao, Juan. "Role of ATM in T Cell Dysfunction During Chronic Viral Infections." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etd/3531.
Full textAbstract:
Hepatitis C virus (HCV) or human immunodeficiency virus (HIV) infection leads to a phenomenon of inflammaging, in which chronic infection or inflammation induces an immune aged phenotype with T cell dysfunction. Thus, HCV or HIV infection has been deemed as a model to study the mechanisms of T cell infammaging and viral persistence in humans. In this dissertation, T cell homeostasis, DNA damage and repair machineries were investigated in patients with chronic HCV or HIV infection at risk for inflammaging. We found a significant depletion in CD4 T cells, which was correlated with their apoptosis in chronically HCV/HIVinfected patients, compared to age-matched healthy subjects. In addition, virus-infected patients’ CD4 T cells were prone to DNA damage that extended to chromosome ends (telomeres), leading to accelerated telomere erosion - a hallmark of senescence. Mechanistically, the DNA doublestrand break (DSB) sensor MRE11, RAD50, and NBS1 (MRN) remained intact, but the DNA damage checkpoint kinase ataxia telangiectasia mutated (ATM) and its downstream checkpoint kinase 2 (CHK2) were significantly suppressed in T cells from HCV/HIV-infected individuals. Consistently, ATM/CHK2 activation, DNA repair, and cellular functions were also impaired in primary CD4 T cells following ATM knockdown, or exposure to the ATM inhibitor (KU60019), as well as in CD4 T cells co-cultured with HCV-infected hepatocytes, or a T cell line infected with HIV-1 in the presence of raltegravir in vitro, which recapitulates the biological effects observed in T cells in the setting of HCV/HIV infection in vivo. Importantly, ectopic expression of ATM was essential and sufficient to reduce the DNA damage, survival deficit, and cellular dysfunction in T cells from both HCV and HIV-infected individuals. These results demonstrate that failure of DSB repair due to ATM deficiency leads to unrepaired DNA damage and renders virally infected patients’ T cells prone to senescence and apoptosis, thus contributing to CD4 T cell loss or dysfunction during chronic HCV or HIV infection. This study reveals a novel mechanism by which ATM deficiency promotes telomeric DNA damage and premature T cell aging, and provides a new therapeutic target for inflammaging-induced immune dysfunction during chronic viral infection.
43
Lamontagne-Blouin, Christopher. "Modulation of T cell antigen receptor signaling in CD8+ T lymphocytes following priming with homeostatic and inflammatory cytokines." Mémoire, Université de Sherbrooke, 2012. http://hdl.handle.net/11143/6325.
Full textAbstract:
La stimulation de cellules T naïves nécessite du déclenchement de la signalisation par l'intermédiaire du récepteur d'antigène de cellule T (TCR) ainsi que l'activation simultanée des récepteurs de co-stimulation. Toutefois, les cellules T CD8+ naïves peuvent proliférer de façon antigène-indépendants suite à la stimulation synergique par certaines cytokines homéostatiques (IL-7 ou IL-15) et inflammatoires (IL-6 ou IL-21). Ces cellules pré-stimulées prolifèrent même à des faibles concentrations d'antigènes ou en présence d’agonistes du TCR. Ceci leur permet de sécréter des cytokines effectrices, d'être plus spécifiques à leur antigène et d’avoir une activité cytolytique plus importante. Les mécanismes déclenchés par les cellules T CD8+ permettant une sensibilité accrue à l'antigène suite à la "pré-stimulation aux cytokines" n'ont pas encore été élucidés. Nous avons utilisé trois différents modèles de souris transgéniques portant le TCR P14, PMEL ou 8.3-NOD sur les lymphocytes T CD8+ afin d’étudier les mécanismes moléculaires suite à la pré-stimulation aux cytokines. Les cellules T CD8+ portant le TCR transgénique amorcées avec les cytokines, possèdent une augmentation globale des protéines tyrosine-phosphorylés après stimulation du TCR par rapport aux cellules naïves. Cette augmentation de la phosphorylation de la protéine tyrosine a été associée à une augmentation de l'expression de CD8, et a été moins prononcé lorsque CD8 a également été réticulés avec le TCR. Ceci suggère que l'amorçage aux cytokines peut prédisposer le TCR et CD8 à colocaliser, ce qui renforcerait la phosphorylation des chaînes du TCR par la kinase Lck associée à CD8. Les lymphocytes T CD8+ amorcées aux cytokines présentent également des quantités accrues de radeaux lipidiques plasmatiques à la membrane, qui organisent la plate-forme de signalisation du TCR au cours de la stimulation antigénique. L’amorçage aux cytokines des lymphocytes T CD8+ a également augmenté la localisation de CD45, une phosphatase qui diminue l’inhibition automatique de la Lck dans les radeaux lipidiques. Cependant, l'amorçage aux cytokines n'a pas d'incidence sur la capacité des cellules CD8+ T pour former des conjugués avec les cellules présentatrices d'antigène puisées avec des peptides apparentés. En conclusion, ces résultats suggèrent que la composition et les fonctions des radeaux lipidiques peuvent moduler la sensibilité à l'antigène via le TCR lorsque les lymphocytes T CD8+ ont été pré-stimulés aux cytokines.
44
Chomka, Agnieszka. "The role of interleukin 33 in intestinal homeostasis." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:5feac0c6-a417-4170-8bce-37318b7d9be9.
Full textAbstract:
IL-33 is a pleiotropic cytokine that orchestrates both innate and adaptive immunity. It is commonly associated with type 2 immune responses but recently expression of the IL-33 receptor, ST2, was reported on Treg cells found preferentially in non-lymphoid tissues, such as the visceral adipose tissue, muscle or colon. A crucial role of Tregs in maintaining intestinal homeostasis has been well described. However, little is known about the functional relevance of the ST2-expressing Treg population in the colon. Phenotypic and functional characterisation of Tregs in the gut revealed the presence of two distinct populations: ST2+/Gata3+ and Rorγt+ Tregs. Thymic-derived ST2+/Gata3+ Tregs showed a more activated phenotype and produced IL-10 under homeostatic conditions. Upon microbial challenge and colitis, ST2+/Gata3+ Tregs were decreased, while Rorγt+ Tregs expanded. Furthermore, in vitro experiments demonstrated that IL-33 directly induced activation of the Gata3 pathway in Tregs, which enhanced expression of Foxp3 and ST2. Additionally, amphiregulin was also induced in Tregs upon stimulation with IL-33. However, in vivo, IL-33 was dispensable for both the maintenance of Treg cells under homeostatic conditions and Treg function in Helicobacter hepaticus-driven colitis. Investigation of the negative regulators of IL-33 showed that IL-23 inhibited IL-33-mediated effects on Tregs. We also observed increased production of soluble ST2 by stromal cells during intestinal inflammation, which likely contributed to the reduction of IL-33 bioavailability. Finally, a systematic analysis of the cellular source of IL-33 revealed that PDGRFα+ stromal cells located in the T cell zone of secondary and tertiary lymphoid tissues were a major IL-33-producing cell population in the gut. Collectively, our findings suggest that signals received by the stromal compartment upon cell injury may trigger a specific phenotype of Tregs with a repair capacity, and thus, promote intestinal homeostasis. These findings improve our understanding of tissue-resident Tregs and open an exciting avenue to explore heterocellular signalling between stromal cells and Tregs.
45
Acero, Luis F. "T-cell homeostasis and the role of the pro-apoptotic Bcl-2 family member Bim." Cincinnati, Ohio : University of Cincinnati, 2005. http://www.ohiolink.edu/etd/view.cgi?acc%5Fnum=ucin1126725924.
Full text
46
Plaza, Sirvent Carlos [Verfasser], and Ingo [Akademischer Betreuer] Schmitz. "The role of cFLIP in regulatory T cell homeostasis / Carlos Plaza Sirvent. Betreuer: Ingo Schmitz." Magdeburg : Universitätsbibliothek, 2015. http://d-nb.info/1083811886/34.
Full text
47
ACERO, LUIS FERNANDO JR. "T-CELL HOMEOSTASIS AND THE ROLE OF THE PRO-APOPTOTIC Bc1-2 FAMILY MEMBER Bim." University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1126725924.
Full text
48
Reynolds, Joseph Benjamin. "Mathematical models of the roles of IL-2 and IL-7 in T cell homeostasis." Thesis, University of Leeds, 2014. http://etheses.whiterose.ac.uk/6832/.
Full textAbstract:
We study the homeostasis of a peripheral naive T cell population through the use of deterministic mathematical models. A two compartment approach is used, where, naive T cells are assumed to be either in a resting state, or undergoing the cell cycle. We begin by assuming all rates are linear, then discuss the limitations in doing so. We next explore examples of published methods which improve this simple description. Finally, we introduce a model in which resting T cell survival and entry into the cell cycle is assumed to be dependent on the amount of available IL-7. To aid our description of T cell homeostasis, a stochastic model of IL-7 signalling is developed. In this model we consider the number of IL-7 receptors, either membrane bound or internalised, the extra-cellular concentration of IL-7, and the amount of IL-7 induced signalling. The model is used to derive a relationship between the amount of IL-7 induced signalling to the extra-cellular concentration of IL-7. The survival and proliferative ability of the T cell population is then assumed to be dependent on the amount of IL-7 induced signalling with respect to IL-7 signalling thresholds for survival and division. This signalling relation is then used with the model of T cell homeostasis. The model is fitted to experimental data measuring the expansion of transgenic naive T cells in lymphopenic mice. We show this approach can capture the homeostatic equilibrium, and notably, time scales required to reach equilibrium. The model is then explored in the context of the human periphery. In a separate piece of work we develop a stochastic Markov model of the peripheral CD4+ T cell pool, in which we consider sub-populations of naive, IL-2 producing, IL-2 non-producing and regulatory T cells. The balance between the IL-2 producing and regulatory sub-populations is assumed to be determined by a recently proposed quorum-sensing hypothesis. This model is explored in scenarios where no antigen is presented to the CD4+ population, before and after a challenge, and when antigen is presented at a constant level. We show, amongst other results, that the number of regulatory T cells in equilibrium is greater when antigen is presented, whilst the number of IL-2 producing T cells remains the same. We finally use the stochastic aspect of this model to explore probabilities of and times to extinction of the sub-populations.
49
Mayack, Shane Renee. "The role of Janus Kinase 3 in CD4+ T Cell Homeostasis and Function: A Dissertation." eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/94.
Full textAbstract:
This dissertation addresses the role for Janus Kinase 3 (Jak3) in CD4+ T cell homeostasis and function. Jak3 is a protein tyrosine kinase whose activity is essential for signals mediated by the γc dependent cytokines IL-2, -4, -7, -9, -15, and -21. Previous data have demonstrated that peripheral CD4+ T cells from Jak3-deficient mice have a memory phenotype and are functionally impaired in both proliferative and IL-2 responses in vitro. Interestingly, Jak3/γc activity has been previously shown to play a role in the prevention of T cell anergy.
These studies were initiated to more precisely define the role for Jak3/γc cytokines in the prevention of T cell anergy and the maintenance of functional CD4+ T cell responses. We began to address this question by assessing global gene expression changes between wild type and Jak3-/- CD4+ T cells. These data indicate that Jak3-/- CD4+ T cells have an increase in gene expression levels of inhibitory surface receptors as well as immunosuppressive cytokines.
Further analyses confirmed that Jak3-deficient T cells express high levels of PD-1, secrete a Trl-type cytokine profile following direct ex vivo activation, and suppress the proliferation of wild type T cells in vitro. These characteristics indicate that CD4+ Jak3-/- T cells share properties with regulatory T cell subsets that have an important role in peripheral tolerance and the prevention of autoimmunity.
We next addressed whether these regulatory characteristics were T cell intrinsic or rather the result of expanding in a Jak3-deficient microenvironment characterized by a number of immune abnormalities and a disrupted splenic architecture. Jak3-/- CD4+ T cells proliferate in vivoin a lymphopenic environment and selectively acquire regulatory T cell characteristics in the absence of any additional activation signals. While the precise mechanism by which Jak3-deficient T cells acquire these characteristics remains unclear, our data indicate that one important component is a T cell-intrinsic requirement for Jak3 signaling.
These findings indicate several interesting aspects of T cell biology. First, these studies, demonstrate that the homeostatic proliferation of CD4+ T cells is not dependent on signaling via γc-dependent cytokine receptors. And, second, that the weak activation signals normally associated with homeostatic expansion are sufficient to drive Jak3-/- T cells into a non-conventional differentiation program. Previous data indicate that, for wild type T cells, signaling through both the TCR as well as γc-dependent cytokine receptors promote the homeostatic proliferation of T cells in lymphopenic hosts. Since Jak3-/- T cells are unable to receive these cytokine signals, their proliferation is likely to be wholly dependent on TCR signaling. As a consequence of this TCR signaling, Jak3-/- T cells proliferate, but in addition, are induced to up regulate PD-1 and to selectively activate the IL-10 locus while shutting off the production of IL-2. Since this fate does not occur for wild type T cells in a comparable environment, it is likely that the unique differentiation pathway taken by Jak3-/- T cells reflects the effects of TCR signaling in the absence of γc-dependent cytokine signaling.
Interestingly, wild type T cells undergoing homeostatic expansion in lymphopenic hosts show many common patterns of gene expression to freshly-purified unmanipulated Jak3-/- T cells. For instance, micro array analysis of gene expression in wild type CD4+ T cells after lymphopenia induced homeostatic expansion show a similar pattern of upregulation in surface markers (PD-1 and LAG-3), and cytokine signaling molecules (IL-10 and IFN-γ cytokine, receptors, and inducible gene targets) to that of Jak3-/- CD4+ T cells immediately ex vivo. These data suggest that the process of homeostatic proliferation normally induces immune attenuation and peripheral tolerance mechanisms, but that full differentiation into a regulatory T cell phenotype is prevented by γc-dependent cytokine signals.
Taken together these data suggest that Jak3 plays an important role in tempering typical immune attenuation mechanisms employed to maintain T cell homeostasis and peripheral tolerance.
50
Metidji, Amina. "Type I interferons and T regulatory cells : effects on development, homeostasis and function." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066058/document.
Full textAbstract:
L'interféron de type I (IFN) est une famille de cytokine avec des propriétés antivirales et immunomodulatrices. Alors que les effets antiviraux de l'IFN sont bien caractérisés, leurs propriétés immunomodulatrices le sont moins. Nous avons examiné en profondeur les effets de l'IFN de type I sur le développement, l'homéostasie, et la fonction des cellules Treg. Nous avons utilisé des souris chimériques reconstituées avec une mixture de moelle osseuse de souris normale (WT) et de souris sans le récepteur de l'IFN(IFNAR)KO, et des souris femelles hétérozygotes exprimant une délétion d'IFNAR spécifiquement sur les Treg. Dans ces deux modèles, la signalisation d'IFNAR favorise le développement de la lignée Treg dans le thymus et leur survie dans la périphérie. Nous avons également généré des souris chimériques en utilisant le foie f¿tal de souris scurfy, les Treg dérivés de IFNAR KO ont été incapables de contrôler l'activation des cellules T effectrices et l'inflammation des tissus. Nous avons aussi examiné les effets pendant l'infection avec le virus chorioméningite lymphocytaire chronique (LCMV). Nous avons démontré que le pourcentage de V?5+ Treg était significativement réduit chez les souris IFNAR KO. Nous avons également examiné l'effet pendant Encéphalomyélite auto-immune expérimentale (EAE). Suite à l'induction de l'EAE, les souris chimériques WT/IFNAR KO développent une maladie plus sévère que les souris WT/WT. Nous montrons aussi que les souris avec une délétion conditionnelle de IFNAR dans les Tregs développent une forme très grave de l'EAE. Ces résultats démontrent que la signalisation via IFNAR est nécessaire pour la fonction de suppressive des Treg dans l'EAEType I Interferons (IFNs) are a family of cytokines with antiviral and immunomodulatory properties. While the antiviral effects of IFNs are well characterized, their immunomodulatory properties are less clear. We examined the effects of type I IFN on development, homeostasis, and function of Treg cells. We used mixed bone marrow (BM) chimeras between WT and IFNαβ receptor (IFNAR) KO mice, and heterozygous female mice expressing a Treg-specific deletion of the IFNAR. IFNAR signaling promoted the development of the Treg lineage in the thymus and their survival in the periphery. IFNAR KO Treg from chimeric mice displayed a more naïve phenotype. In mixed chimeras with Scurfy fetal liver, Treg derived from IFNAR KO BM were unable to control T effector cell activation and tissue inflammation. We also examined the potential effects during Chronic Lymphocytic Choriomeningitis Virus infection. We demonstrated that the percentage of Vβ5+ Treg was significantly reduced in IFNAR KO mice, and that the IFNAR functions in a Treg cell intrinsic manner. We also studied the effect during Experimental autoimmune encephalomyelitis (EAE). Following induction of EAE, WT / IFNAR KO chimeras develop more severe disease than the WT/WT chimeras. Mice with a conditional deletion of the IFNAR in Treg rapidly developed a very severe form of EAE. These results demonstrate that signaling via the IFNAR is required for Treg suppressor function in EAE. Collectively, these studies demonstrate that under certain condition including stress, chronic infection, and autoimmune disease, IFNAR signaling is essential to maintain Treg development, homeostasis, and function