Dissertations / Theses on the topic 'Follicular T cells'
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Trüb, Marta. "Follicular T helper cell populations." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/20466.
Sayin, Ismail. "Characterization of human T follicular regulatory cells." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1560336991188191.
Misiak, Jan. "The interactions of stromal cells and follicular helper T cells resulting in a B-cell supporting, IL4-producing phenotype in the context of follicular lymphoma." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B030.
The enrichment of the microenvironment with tumor-promoting interleukin 4 (IL4) has been implicated in the pathogenesis of follicular lymphoma (FL) and was found to be conferred mainly by T follicular helper (Tfh) cells. In this study, we investigated the bidirectional crosstalk of fibroblastic reticular cells that are expanded in FL and Tfh cells with the analysis of gene expression profiles of the respective, and an in-vitro co-culture model of human induced FRC-like cells. We demonstrated that FRC-like cells enhance the growth of Tfh cell subsets in vitro. Crucially, we uncovered a specific upregulation of IL-4 secretion by precursor Tfh (pre-Tfh) cells co-cultured with FRC-like cells. Additionally, we demonstrated that Notch and ICAM1/LFA1 are two pathways involved in IL-4 secretion following FRClike cell / Tfh cell crosstalk. This observation was particularly interesting in FL context, because FL pre-Tfh cells display an enriched Notch and integrin gene expression profile as well as an overexpression of IL-4, compared to their tonsil counterpart. Altogether, we described new interactions between stromal cells and Tfh subsets and uncovered a specific cytokine profile modification at pre-Tfh stage after contact with FRC-like cells that could explain the high levels of IL-4 in FL and provide a novel target for therapy
Vanderleyden, Ine. "Follicular regulatory T cell migration and differentiation." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/288422.
Wang, Changna. "Follicular Dendritic Cells, Resting CD4+ T Cells and Human Immunodeficiency Virus Expression." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/2906.
Pandey, Shubham. "Identification of Interleukin 4 - CXCL12 supportive loop in follicular lymphoma." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B031/document.
Follicular lymphoma (FL) is the most frequent indolent B-cell lymphoma. Beside recurrent genetic alterations, tumor microenvironment, including lymphoid stromal cells, has been shown to play a key role in FL development. However, in situ characterization of lymphoid stromal cells is still lacking in humans and there are very few studies focusing on the factors that could lead to stroma polarization in normal and pathological context. In this thesis, we showed first that in FL, lymph node (LN) and bone marrow (BM) infiltrating stromal cells highly express the chemokine CXCL12. We next focused on the mechanisms underlying this upregulation. Interestingly, whereas malignant FL B cells induced overexpression of CCL2 in stromal cells in a TNF-dependent manner, they did not contribute to CXCL12 induction. Conversely, FL-infiltrating follicular helper T cells (FL-TFH), the key FL-supportive T-cell subset could trigger CXCL12 expression in stromal cells. IL-4 is the main FL-TFH-derived cytokine and showed a positive correlation with CXCL12 expression inside FL cell niches. Moreover, based on our in vitro lymphoid stroma differentiation model, we demonstrated that IL-4 promoted CXCL12 expression in stromal cells, together with a phenotype close to that identified in situ within FL cell niche. Such IL4 dependent CXCL12 regulation is more pronounced in stromal cells already committed towards lymphoid stromal cells by a prestimulation by TNF/LT in association with an increased STAT6 activation. These data were validated in a model of ectopic lymphoid organ formation in mice. Finally, CXCL12 induced FL B-cell migration, and adhesion to stromal cells through the activation of a signaling pathway that could be abrogated by the Btk inhibitor Ibrutinib. These data argue for considering IL-4/CXCL12 axis as a potential therapeutic target to disrupt FL protective cell niche in this still fatal malignancy
Kawamoto, Shimpei. "Preferential Generation of Follicular B Helper T Cells from Foxp3+ T Cells in Gut Peyer's Patches." Kyoto University, 2011. http://hdl.handle.net/2433/142110.
Thomas, Jessica. "T follicular helper cells in health and inflammatory bowel disease." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/t-follicular-helper-cells-in-health-and-inflammatory-bowel-disease(1c45e306-6a7b-4d84-b02f-e4e1c500dbea).html.
Townsend, William Mathew. "A study of CD4+ follicular helper T cells in the follicular lymphoma microenvironment and normal germinal centres." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/a-study-of-cd4-follicular-helper-t-cells-in-the-follicular-lymphoma-microenvironment-and-normal-germinal-centres(744b7c2f-f848-4c41-8fd1-687dc2201f6b).html.
Rasheed, Mohammed Ata Ur. "Gene signatures and functional analysis of follicular B helper T cells." [S.l.] : [s.n.], 2006. http://www.diss.fu-berlin.de/2006/538/index.html.
Sabir, Suleman Rahman. "Dissecting the role of T-follicular helper cells in experimental atherosclerosis." Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/7665/.
Wallin, Elizabeth. "The germinal centre reaction and follicular T cells in alloantibody formation." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:e4ecdd13-7c1e-4d4e-8491-8a22857cdb86.
Pfeilschifter, Janina Marie. "Targeting B non-Hodgkin lymphoma and tumor-supportive follicular helper T cells with anti-CXCR5 CAR T cells." Doctoral thesis, Humboldt-Universität zu Berlin, 2021. http://dx.doi.org/10.18452/23169.
CAR T cell therapy is a promising new treatment option for patients suffering from aggressive B non-Hodgkin lymphomas (NHLs). In CAR T cell therapy, patient-derived T cells are genetically modified to express a chimeric receptor commonly directed towards a surface antigen expressed by neoplastic cells. In this thesis, anti-CXCR5 CAR T cell therapy was investigated as an alternative to anti-CD19 CAR T cell therapy for the treatment of mature B-NHLs. CXCR5 is a B cell homing receptor expressed by mature B cells and follicular helper T (TFH) cells. TFH cells were described to support the tumor cells in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). This expression pattern allows simultaneous targeting of the malignant cells and the tumor-supporting microenvironment by CAR T cell therapy against a chemokine receptor in an unprecedented manner. Main findings included that (1) anti-CXCR5 CAR T cells targeted specifically CXCR5 expressing mature B-NHL cell lines and patient samples in vitro and showed strong in vivo anti-tumor reactivity in an immunodeficient xenograft mouse model, (2) anti-CXCR5 CAR T cells targeted tumor-supportive TFH cells derived from CLL and FL patient samples in vitro and (3) CXCR5 showed a safe expression profile. CXCR5 was strongly and frequently expressed by B-NHLs and its expression on healthy tissue was restricted to lymphoid cells. In summary, anti-CXCR5 CAR T cell therapy presents a novel treatment option for patients suffering from mature B-NHLs by eliminating the tumor and part of the tumor-supportive microenvironment. The second part of the project, the Eμ-Tcl1 murine lymphoma model, which mimics human CLL, was used to study the impact of lymphomagenesis on CXCR5+ T cells. Using single cell RNA sequencing, a profound influence of lymphoma growth on the T cell compartment in Eμ-Tcl1 tumor-challenged mice could be shown.
Miles, Brodie, Shannon M. Miller, and Elizabeth Connick. "CD4 T Follicular Helper and Regulatory Cell Dynamics and Function in HIV Infection." FRONTIERS MEDIA SA, 2016. http://hdl.handle.net/10150/622733.
Weber, Jan Phillip [Verfasser]. "Generation, Maintenance and Fate of T Follicular Helper Cells / Jan Phillip Weber." Berlin : Freie Universität Berlin, 2013. http://d-nb.info/1042940827/34.
Blackburn, Matthew James. "Characterization of a CD4 T cell population enriched in T follicular helper cells in macaques during chronic SIV infection." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12055.
A preventive vaccine for HIV infection is urgently needed to curb the HIV/AIDS pandemic. To date only one human trial testing the combination of an ALVAC-HIV/gp120 protein strategy (Thai trail) has resulted in some protection from HIV infection. The correlate of protection elicited by this vaccine strategy was non-neutralizing antibodies to the gp120 protein. Nevertheless, the overall efficacy of the Thai trial was limited (31.2%); indicating that more work needs to be performed to ameliorate the Thai trial vaccine efficacy. T Follicular Helper (TFH) cells are subset of CD4 T cells that localize within the follicular region of lymph nodes, are required for the formation and maintenance of the germinal center, and provide help to B cells. TFH may therefore be critical for the development of effective antibodies to HIV/SIV. Here, we characterize TFH in different lymphoid compartments of naïve and infected rhesus macaques, the preferred animal model to assess the efficacy of candidate vaccines for HIV. First, we looked at the frequency of TFH within the various lymphoid compartments. TFH, characterized as PD-1++, ICOS++ and CCR7-, were higher within the spleen, the lamina propria of the rectal mucosa, and the tonsils than the lymph nodes. Interestingly, during chronic SIV infection, the frequency of TFH significantly increased in the lymph nodes while remaining fairly constant in the spleen. We then functionally characterized TFH in the lymph nodes of infected and non-infected macaques by performing an intracellular cytokine staining to measure the production of IFN-γ, TNF-α, IL-17, and IL-21 after in vitro stimulation with PMA-ionomycin and SIV-env and SIV-gag overlapping peptides. Interestingly, while TFH (CCR7-/PD-1++) and non-TFH were capable of producing IFN-γ, TNF-α and IL-21 after stimulation with PMA- ionomycin, in chronically infected animals, we observed an impaired production of IL-21. As localization in the germinal center is believed to be relevant for TFH functionality, we established a migrational assay as a way to better discriminate TFH from non-TFH in macaques. The aim was to mimic the in vivo migration of non-TFH to the T cell zone and of TFH to the B cell zone of the lymph nodes, induced by CCL19/CCL21, and CXCL13, respectively, using a two-step assay. We obtained an enrichment of phenotypic defined non-TFH (first migration: CCL19/CCL21) and TFH cells (second migration: CXCL13) from lymph nodes from both naïve and infected macaques. We show that CD4 T cells from naïve macaques that migrated to the CXCL13 had higher levels of Bcl-6 expression and were capable of producing higher levels of IL-21 and lower levels of IFN-γ than cells that migrated to the CCL19 and CCL21-T zone chemokines. Additionally, in SIV infected macaques, CD4 T cells that migrated to CXCL13 were impaired in the production of IL-21 following stimulation with PMA- ionomycin. These results validate our two-step migration assay as an innovative way to study TFH in macaques.
Asrir, Assia. "Caractérisation phénotypique et fonctionnelle des différentes populations de Lymphocytes T CD4 Folliculaires Mémoires." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30084/document.
T Helper Follicular (TFH) cells form a distinct lineage of helper T cells and they specifically control B cells and memory B cell generation. While these cells were considered as effector cells, recently it was identified in Human and in mouse, the existence of memory TFH cells. Memory TFH cells, as CD4 memory T cells, are necessary in case of antigen (Ag) rechallenge to establish a fast, efficient and high affinity Antibody (Ab) response. Indeed, their presence is correlated with the generation and the long-term maintenance of high affinity Ac during viral infections. Moreover, recent studies have shown that analysis of memory TFH cells in the blood may provide clues to understanding the mode of action of vaccines and the pathogenesis of autoimmune diseases. In addition, in the context of many diseases, recent works have also suggested that the frequency and phenotype of memory TFH cells in the blood could serve as a biomarker for diagnosis. Likewise to memory B cells that are subdivided into different cell populations based on their location and the nature of their Ab, different populations of memory TFH cells have recently been identified. Some are in secondary lymphoid organs (SLO) draining the site of immunization, vaccination or infection, or circulating in the non-draining SLO or near the long-lived plasma cells (PC) in bone marrow (BM). These observations raise the question of their phenotypes, functional differences and interactions with the different subsets of memory B cells. The aim of my thesis was to study the phenotypic and functional heterogeneity between the different subsets of memory TFH cells. Due to the heterogeneity of memory B cells (draining lymph nodes or non-draining spleen) and long-lived PCs (BM), we also evaluated the cellular and functional interaction that occurs between these different memories populations. In this context, we have developed a unique experimental model of protein vaccination in unmodified wild-type mice. Specifically, after immunization, we evaluated the development of memory TFH cells and memory B cells specific for the same Ag in the draining SLO and circulating in the spleen and BM. We demonstrated that local memory TFH cells (that reside in the draining SLO) exhibit a more polarized phenotype than their circulating counterparts (present in non-draining SLO)
Pfeilschifter, Janina Marie [Verfasser]. "Targeting B non-Hodgkin lymphoma and tumor-supportive follicular helper T cells with anti-CXCR5 CAR T cells / Janina Marie Pfeilschifter." Berlin : Humboldt-Universität zu Berlin, 2021. http://d-nb.info/1241116989/34.
Alexander, Carla-Maria Alana. "T regulatory cells and the germinal center." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1117.
Le, Thi Kieu Suong. "Caractérisation phénotypique et fonctionnelle des lymphocytes T infiltrants dans les lymphomes B humains." Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM5006.
B-cell lymphomas represent a heterogeneous group of cancers that affect B cells in the lymphatic system. It has become evidence that malignant B cells depend on various interactions with microenvironmental immune cells for their development. Our study focuses on characterization of intra-tumoral T cells in order to understand their contribution in pathogenesis and their therapeutic potentials in the most frequent B cell-lymphoma such as Diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma (FL) and classical Hodgkin lymphoma (cHL).During this work, we have demonstrated a significant quantitative and qualitative difference between different B-cell lymphoma immune composition, especially between their intra-tumoral T cells. FL is characterized by the accumulation of regulatory T cells (Tregs) expressing ICOS, with ability to suppress lymphoma B cells. Generation of Tregs ICOS+ is prompted by cell contact with the lymphoma B cells expressing ICOSL. On the other hand, DLBCL have high level of TCD8 coexpressing PD1 and TIM3 displaying an exhaustion state, which proportion is correlated with their dysfunction level and with their responsiveness to inhibitor receptors blockade. Finally, in some B-cell lymphoma cases, especially cHL, we found the existence of a TCD8 subset, called TFH-like due to their phenotypic and functional similarity with follicular helper T cells (TFH).These data show heterogeneity of immune components between the different B lymphomas, and give opportunity for targeted therapy in lymphoma treatment
Ollerton, Matthew T. "Capacity of Human Immunodeficiency Virus Targeting Chimeric Antigen Receptor T Cells to Eliminate Follicular Dendritic Cells Bearing Human Immunodeficiency Virus Immune Complexes." BYU ScholarsArchive, 2017. https://scholarsarchive.byu.edu/etd/7240.
PODESTA', MANUEL ALFREDO. "STEPWISE DIFFERENTIATION OF IL21-PRODUCING FOLLICULAR HELPER T CELLS REVEALS DISTINCT DEVELOPMENTAL AND FUNCTIONAL STATES." Doctoral thesis, Università degli Studi di Milano, 2023. https://hdl.handle.net/2434/951499.
Abduh, Maisa. "Follicular CD4 T Cells Tutor CD8 Early Memory Precursors : an Initiatory Journey to the Frontier of B Cell Territory." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS371.
Antigen-specific CD8 T cells are involved in the adaptive immune response and play a critical role in protecting the host from infection by intracellular pathogens. This long-lasting protection depends on the generation of memory CD8+ T cell responses, which are highly functional in terms of frequency and functionality, after secondary infection.Following antigen activation, a naive CD8 T cell undergoes strong clonal expansion, generating a heterogeneous population of activated cells that is dominated, at the peak of expansion, by short-lived CD8 effectors (SLECs). This expansion is followed by a phase of drastic contraction through massive apoptosis. A few cells survive this contraction phase and eventually become highly competent memory cells. Precisely when and how these memory precursors (MPECs) are generated is largely unknown, and so are the subsequent steps of their maturation into fully functional memory cells. Help signals from CD4+ T cells are clearly required throughout the MPEC maturation process.Our team has previously shown that FoxP3+ regulatory CD4+ T cells (Tregs) favor MPECs maturation by limiting exposure to IL-2 and by providing inhibitory signals, but this is probably only one facet of the complex and multifaceted help provided by CD4+ T cells to MPEC, and Tregs act on pre-existing MPECs.B-cell memory and CD8+ T cell memory share some common features, such as the expression of the transcription factor Bcl-6. Tfh are major producers of the cytokine IL-21. The mechanisms by which Tfh induces Bcl-6 in B-cells need to be clarified, they might include IL-21 and CD40-CD40L.In this PhD project, we have investigated the potential role of Tfh on the initiation of CD8 memory differentiation, in transgenic mice models, allowing transient and selective depletion of Tfh cells, infected by recombinant Listeria monocytogenes-OVA.We have shown that as early as 2 days after infection, very early memory precursors can be identified by their expression of the chemokine receptor CXCR5. These early precursors, which have an effector phenotype, expand and temporarily migrate to the junction of T-cell and B-cell zones, where they interact with follicular CD4 T cells (Tfh) then lose their CXCR5 expression.Remarkably, this interaction with Tfh, hitherto considered as exclusive B-cell helpers, is required for memory precursors to become competent memory cells responsive to IL-21 and capable of mounting efficient cytotoxic secondary effector responses.This study thus unveils critical early steps in the generation of CD8 memory, identifies CXCR5 as the earliest known marker of CD8 memory precursors, reveals a major helper role for Tfh, and points to possible coordination, through Tfh, between the pathways of CD8 and B-cell memory generation. These findings may have implications for vaccine and immunotherapy design
Aoki, Nobuhiro. "Dysregulated generation of follicular helper T cells in the spleen triggers fatal autoimmune hepatitis in mice." Kyoto University, 2011. http://hdl.handle.net/2433/142096.
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.
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.
Huber, Johanna Elisabeth [Verfasser], and Dirk [Akademischer Betreuer] Baumjohann. "Human circulating T follicular helper cells during viral infection and autoimmunity / Johanna Elisabeth Huber ; Betreuer: Dirk Baumjohann." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1226092527/34.
Miles, Brodie, Shannon M. Miller, Joy M. Folkvord, David N. Levy, Eva G. Rakasz, Pamela J. Skinner, and Elizabeth Connick. "Follicular Regulatory CD8 T Cells Impair the Germinal Center Response in SIV and Ex Vivo HIV Infection." PUBLIC LIBRARY SCIENCE, 2016. http://hdl.handle.net/10150/622413.
Gu-Trantien, Chunyan. "Gene expression profiling of CD4+ T cells infiltrating human breast carcinomas identified CXCL13-producing T follicular helper cells associated with tertiary lymphoid structures and better patient outcome." Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209474.
Over the past decade, studies using murine models have led to the demonstration that CD4+ T helper (Th) cells play a critical role in the control of cancer progression. Additional support for their importance comes from the growing body of recent clinical/translational research data demonstrating the importance of tumor-infiltrating T and B lymphocytes in long-term patient survival for various types of cancer, including breast cancer (BC). As the key population coordinating adaptive immune responses, the role(s) played by individual Th subsets in cancer immunity remains largely controversial. The Th1 subset has uniquely been shown to have a clear anti-tumor effect, guiding CD8+ cytotoxic T cells-mediated direct tumor cell lysis through IFN-γ secretion. Although the negative regulatory role played by Treg cells has been extensively studied in cancer, its prognostic value along with that of Th2 and Th17 cells have not been clearly demonstrated in patients. T follicular helper (Tfh) cells, a recently characterized Th subset that plays a primary role in the generation of B cell memory in secondary lymphoid organs, have not been previously described infiltrating solid tumors. The principal objective of this thesis was to perform an in-depth characterization of tumor-infiltrating CD4+ T cells (TIL) and Th subsets in human BC, where very little is currently known.
Using whole genome microarrays, we analyzed the gene expression profiles of TIL relative to their counterparts from the axillary lymph nodes and peripheral blood. Applying a novel approach, we compared TIL profiles with public microarray data for Th subsets, demonstrating: 1) the presence of all major Th subsets (Th1, Th2, Th17, Treg as well as Tfh) in the TIL, 2) the TIL are effector memory rather than central memory cells, 3) the TIL are concomitantly activated and suppressed and 4) TIL from tumors with extensive lymphoid infiltrates are more activated/less suppressed in the TCR/CD3 signaling pathway, producing higher levels and a wider panel of Th cytokines than TIL from minimally-infiltrated tumors.
We also performed in vitro experiments to study tumor microenvironment effects on TIL by treating normal CD4+ T cells from healthy donor blood with primary tumor supernatants (SN). Tumor SN largely reproduces the TIL profile in normal Th cells, totally suppressing their activation and inhibiting their cytokine production. Intriguingly, the highly restricted number of cytokines induced by tumor SN included several tumor-promoting factors, such as IL-8 and TNF. SN from an extensively-infiltrated tumor was found to be less immune-suppressive than SN from minimally-infiltrated tumors. In line with this, TIL from minimally-infiltrated tumors are closer to SN-treated (suppressed) activated donor cells whereas TIL from extensively-infiltrated tumors are more similar to activated cells without SN treatment.
These results led us to further investigate the observed differences between TIL from extensive and minimally-infiltrated tumors. Genes characterizing Th1 and Tfh cells were enriched in the extensively-infiltrated tumors. PD-1hiCD200hi Tfh cells were specifically detected in extensively-infiltrated tumors by flow cytometry and these cells were determined to be the major source of the chemokine CXCL13. Immunohistochemical analysis demonstrated highly-organized tertiary lymphoid structures (TLS) within the tumor, containing a CD4+/CD8+ T cell zone and a B cell zone with reactive germinal centers where Tfh cells and follicular dendritic cells (FDC) are resident. Their presence suggests the origin of an effective memory anti-tumor immune response.
Finally, we generated Tfh- and Th1-specific gene signatures reflecting differences between extensive and minimal TIL and tested their prognostic value in large-patient-scale public data sets. Our Tfh signature predicts better 10-year disease-free survival for all BC subtypes, outperforming the Th1 signature, suggesting that Tfh cells play a more central role than Th1 cells in anti-tumor immunity. CXCL13 is the determinant gene of our Tfh signature, showing particularly strong prognostic power for the HER2+ subtype. Additionally, these signatures also predict a better response to neoadjuvant chemotherapy.
This thesis research has demonstrated that a previously undetected Th subset, Tfh cells, infiltrates solid tumors and shown that their presence signals enhanced anti-tumor immunity.
Durant cette dernière décennie, des travaux menés dans des modèles murins ont permis de mettre en évidence le rôle crucial joué par les lymphocytes T auxiliaires CD4+ (Th) dans le contrôle de la progression des cancers. De plus, de nombreuses études cliniques et/ou translationnelles récentes corroborent ces observations en montrant une corrélation entre l’importance de l’infiltration intra-tumorale par les lymphocytes T et B et la survie à long terme des patients atteints de différents types de cancer, dont le cancer du sein. En tant que chefs d’orchestre de la réponse immune adaptative, les rôles spécifiques des sous-populations des cellules Th restent controversés. Les Th1 sont la seule population exerçant une claire réponse anti-tumorale, qui est liée à la sécrétion d’IFN-γ, une cytokine primordiale à l’action des lymphocytes T cytotoxiques CD8+. Bien que le rôle néfaste des T régulateurs (Treg) a été largement étudié dans le cancer, leur implication pronostique ainsi que celle des Th2 et Th17 n’ont pas encore été clairement démontrées. La présence d’une sous-population de CD4, les T auxiliaires folliculaires (Tfh), cellules clés dans la différenciation des lymphocytes B mémoires au sein des organes lymphoïdes secondaires, n’a jamais été décrite dans les cancers solides. Le but principal de ce travail est de caractériser les sous-populations des lymphocytes T CD4+ infiltrant la tumeur (TIL) en prenant comme modèle le cancer du sein humain. A l’heure actuelle, il existe très peu de données sur les TIL CD4 dans ce type de cancer.
Nous avons d’abord établi le profil génique des TIL en les comparant avec ceux provenant des ganglions axillaires ou du sang périphérique. En appliquant une nouvelle approche, nous avons comparé les profils des TIL avec les données publiques de sous-populations de Th et démontré que :1) toutes les sous-populations de cellules Th (Th1, Th2, Th17, Treg et Tfh) infiltrent la tumeur, 2) les TIL ont un phénotype plus proche de celui des cellules mémoires effectrices que des cellules mémoires centrales, 3) les TIL sont simultanément activés et supprimés et 4) les TIL provenant des tumeurs massivement infiltrées («extensives») par des lymphocytes sont mieux activés et moins supprimés que les TIL des tumeurs peu infiltrées («minimales») dans la voie de signalisation TCR et produisent des cytokines d’une quantité plus élevée et d’une répertoire plus large.
Nous avons également effectué des expériences in vitro pour étudier l’effet de l’environnement tumoral sur les TIL en traitant des CD4 normaux (provenant des donneuses saines) par le surnageant (SN) extrait des tumeurs fraiches. Le SN tumoral induit un profil génique proche de celui des TIL en inhibant l’activation et la production de cytokines de ces cellules stimulées. Curieusement, parmi le peu de cytokines induites par le SN tumoral, des facteurs pro-tumoraux comme IL-8 et TNF sont détectés. Le surnageant provenant d’une tumeur «extensive» est moins immunosuppresseur que ceux des tumeurs «minimales». Conformément, les TIL provenant des tumeurs «minimales» ont un profil génique proche des cellules normales activées et traitées (supprimées) par le SN tumoral tandis que les TIL des tumeurs «extensives» ressemblent aux cellules activées non traitées.
Ces résultats nous avaient guidés à investiguer plus profondément les différences observées entre les TIL des tumeurs «extensives» et «minimales». Les gènes caractéristiques des Th1 et Tfh sont enrichis dans les tumeurs «extensives». Les cellules Tfh PD1hiCD200hi sont spécifiquement détectées par cytométrie de flux dans les tumeurs «extensives» et sont identifiées comme les producteurs principaux de la chimiokine CXCL13. L’examen par immunohistochimie a permis de détecter des structures lymphoïdes tertiaires (TLS) dans la tumeur, composées d’une zone T (CD4 et CD8) et d’une zone B au sein de laquelle se trouve parfois un centre germinatif actif contenant des Tfh et des cellules dendritiques folliculaires (FDC). La présence de ces structures suggère l’origine d’une réponse immune mémoire anti-tumorale.
Finalement, nous avons établi des signatures géniques spécifiques aux Tfh et Th1 et recherché leur impact pronostique dans deux bases de données publiques à grande échelle. Notre signature Tfh est positivement corrélée avec la survie à 10 ans des patientes de tous les sous-types de cancer du sein, et est plus performante que la signature Th1. Ceci suggère que les Tfh pourraient jouer un rôle plus crucial que les Th1 dans la réponse immune anti-tumorale. CXCL13 est le gène déterminant de notre signature Tfh et son expression est fortement associée à une meilleure survie chez les patientes du sous-type HER2+. De plus, ces signatures prévoient également une meilleure réponse à la chimiothérapie néoadjuvante (préopératoire).
Cette étude a démontré qu’une nouvelle sous-population de CD4, les Tfh, infiltre la tumeur solide et leur présence indique l’existence d’une immunité anti-tumorale renforcée.
Doctorat en Sciences biomédicales et pharmaceutiques
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Durand, Mélanie. "Spécialisation fonctionnelle des cellules myéloïdes mononucléaires humaines dans l’induction des réponses T folliculaire helper." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB087/document.
T follicular helper cells (Tfh) play a key role in the establishment of efficient humoral responses. Indeed, Tfh are involved in B lymphocyte selection allowing the development of high affinity memory B cells and antibodies. Tfh are promising targets for new therapeutic strategies, especially to increase the effectiveness of vaccination. Thus, it is crucial to better understand the stages leading to their development, especially in human. Initiation of Tfh polarisation occurs in secondary lymphoid organs and involves mononuclear myeloid cells (MMC). MMC from secondary lymphoid organs include resident macrophages and three subsets of resident Dendritic Cells (DC): cDC1 (CD141+), cDC2 (CD1c+) and pDC. We were particularly interested in human MMC subsets respective roles in the induction of Tfh polarisation. Thus, the work carried out during my thesis aimed first at analysing the ability of different populations of MMC to induce Tfh polarisation, in order to highlight potential functional specialisations. In a second step, we focused on the molecular mechanisms involved in Tfh polarisation by MMC. We have shown a functional specialisation of cDC2 and tonsillar macrophages for Tfh polarisation. However, differences have been observed between cDC2 and macrophages, since macrophages induce secretion by T cells of a large amount of CXCL13 compared to cDC2, which are more effective in inducing IL21 production. We have also been able to show that cDC2 and macrophages secreted cytokines previously shown to play a role in Tfh induction such as IL12p70, ActivinA and TGFβ. In order to confirm the role of these cytokines in Tfh polarisation induced by tonsil MMCs, we used blocking antibodies in our T helper polarisation experiments. Thereby, we confirmed the role of IL12p70, Activin A and TGFβ in the induction of human Tfh. Our results also suggest a role for Activin A and TGFβ in inducing secretion of CXCL13, whereas IL12p70 would be involved in the induction of IL21 secretion. Besides, our results suggest the existence of two Tfh subsets characterised by expression of either IL21 or CXCL13. The work performed during my thesis broadens the knowledge on the functional specialisation of human DC subsets and macrophages, and provides new insight into the differentiation of human Tfh
Gigoux, Mathieu. "The role of inducible costimulator-mediated phosphoinositide 3-kinase activation in the differentiation and function of follicular helper T cells." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121421.
Les anticorps sont des composantes cruciales de l'arsenal que le système immunitaire adaptatif utilise contre les pathogènes invasifs. La production d'anticorps de haute-affinité réarrangés par commutation isotypique nécessite l'apport des lymphocytes T auxiliaires folliculaires (Tfh), un sous-type de lymphocytes T auxiliaires CD4+ qui migrent dans les follicules nodules lymphatiques et y promeuvent la différentiation des cellules B en cellules plasmatiques, le tout durant les réactions du centre germinatif (GC). Le récepteur de costimulation de type CD28 Costimulateur Inductible (ICOS) est exprimé sur la surface des cellules T activées et joue un rôle critique dans la génération de cellules Tfh autant chez la souris que l'humain, cependant les mécanismes moléculaires demeurent inconnus. Jusqu'à présent, ICOS était reconnu comme un puissant activateur de la phosphatidyl inositol-3 kinase (PI3K), mais le rôle de l'activation de PI3K médiée par ICOS dans les cellules T demeure mal compris. Le travail présenté dans cette thèse retrace deux études qui décrivent le rôle unique de PI3K dans la fonction et la différentiation des cellules Tfh médiées par ICOS. Dans la première étude, présenté dans le Chapitre II, j'ai analysé une ligné de souris 'knock-in' possédant une mutation ponctuelle dans la région cytoplasmique de ICOS empêchant ainsi la liaison de PI3K (ICOS-YF). Je démontre que l'activation de PI3K médiée par ICOS demeure cruciale pour la génération de cellules Tfh, ainsi qu'en conséquence la formation des GC, la commutation isotypique d'anticorps et la maturation d'affinité. L'axe ICOS-PI3K s'avère critique pour la potentialisation de l'expression médiée par le récepteur de cellules T (TCR) de IL-21 et IL-4, des cytokines clés impliquées dans l'aide aux cellules B médiée par les cellules T. J'illustre également des résultats qui prouvent que ICOS et CD28 exercent des rôles distinct dans le processus complexe de la différentiation des cellules Tfh, où CD28 est principalement impliqué dans l'expansion précoce des cellules T CD4+ par l'entremise de mécanismes de signalisation indépendants de PI3K, tandis que ICOS s'engage plutôt de façon PI3K-dépendante dans les étapes tardives de la différentiation des cellules Tfh. Dans la seconde étude au Chapitre III, je révèle que la costimulation par ICOS augmente l'activation médiée par le TCR de médiateurs clés de la traduction de 4E-BP1 ainsi que S6K de façon dépendante à PI3K. De façon cohérente, je démontre que l'axe ICOS-PI3K augmente la formation de polysomes sur l'ARN messager d'IL-4. En utilisant un système in-vitro de co-culture de cellules T et B, je fourni des preuves que les cellules T CD4+ mutantes pour ICOS ont une capacité détérioré d'induire la différentiation de cellules B due à une production limitée d'IL-4. Ces découvertes suggèrent que la signalisation par ICOS-PI3K facilite l'acheminement dirigé d'IL-4 d'une cellule T auxiliaire à une cellule B apparentée durant une interaction entre les deux types cellulaires dans le GC. En conclusion, je démontre que PI3K est une composante de signalisation clé en aval de la signalisation par ICOS durant la génération de Tfh. De plus, je prouve que la voix ICOS-PI3K peut modifier l'efficacité de traduction d'ARN messager préexistant suggérant un rôle potentiel d'ICOS dans la régulation de la fonction des cellules Tfh.
Migliori, Edoardo. "The importance of CD4+ follicular helper T cells and tertiary lymphoid structures in the anti-tumor immune response to breast cancer." Doctoral thesis, Universite Libre de Bruxelles, 2017. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/258252.
Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
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Rouers, Angéline. "Impact de l’infection par le virus de l’immunodéficience humaine sur les populations de lymphocytes T folliculaires helper et les réponses B mémoires." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066497/document.
HIV infection is associated with a defect of humoral response. T follicular helper cells (Tfh) support multiple steps of B cell maturation and antibody production. My work was divided in two complementary axes aiming to characterize Tfh and memory B cell responses in HIV-infected patients.I identified several Tfh populations in HIV+ and HIV- spleens by FACS. These three populations were increased in HIV+ spleen. I also evidenced an impact of HIV infection on transcriptional profile and a compromised production of B cell differentiation-related cytokines by splenocytes from HIV+ donors. These results suggest Tfh functions impairment during HIV-infection. In parallel, we noticed an altered maturation of B cells in HIV+ spleens. In a cohort study, we compared memory B cell responses in the blood of Elite controllers (EC) who naturally control HIV and treated HIV+ patients. I evidenced that EC naturally preserve their memory B cell compartments. In contrast to anti-HIV IgG2 and IgG3 secreting B cells, most EC exhibit a high frequency of anti-HIV IgG1 secreting B cells. My work highlights a defective Tfh differentiation, which might explain why B cell maturation is severely affected in HIV-progressors. The status of HIV-controller seems associated with the presence of an IgG1 B cell memory response. Further work will highlight whether Tfh functions are preserved in EC
Trichot, Coline. "Regulation of Human T Helper Cell Diversity : From In Vitro Dendritic Cell-Based Mechanisms to Candidate Biomarkers in Atopic Dermatitis." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS423.
Human immunity is essentially driven by dendritic cells and T helper cells. When dendritic cells detect a pathogen, they will instruct T helper cells to adopt the adapted phenotype for the specific threat encountered. T helper cells are subdivided in multiple subsets, characterized by particular sets of cytokines. Each T helper subset has specific functions and is involved in the clearance of distinct pathogens. If T helper responses are not precisely regulated, they can become pathogenic, in this case T helper pathways can be considered as potential targets for therapy. In this context, I focused my PhD work on studying T helper cell subset diversity and regulation. First, I demonstrated the ability of TSLP-activated dendritic cell to induce T follicular helper cell polarization. Then I participated in building a mathematical model capable of predicting T helper cell response to dendritic-cell derived signals. This model allowed us to identify the specific role of IL-12p70, in an IL-1 context, to induce IL-17F without IL-17A. Finally, I monitered eight T helper and T follicular helper cell populations in peripheral blood from atopic dermatitis patients treated with Dupilumab, an immunotherapy targeting the IL-4 receptor alpha subunit, and was able to show a correlation between decrease of Th17 cell percentage and improvement of EASI clinical score. Overall, my work on Th phenotype diversity provides key mechanistic insight with potential application in immunotherapy
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.
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.
Respect 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
Nuttens, Charles. "Mécanismes impliqués dans la polarisation des lymphocytes T CD4+ folliculaires et l'initiation de l'immunité muqueuse après immunisation intradermique par un antigène particulaire." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066429/document.
The quality of the adaptive immune response to a vaccine is driven by the nature of dendritic cells (DCs) engaged during vaccination. Skin immunization is particularly efficient as it targets the numerous cutaneous DCs, including Langerhans cells (LCs). However, the relationship between DCs and effector cells associated with humoral immunity has not been elucidated. The main objective of my thesis was to identify cellular mechanisms implicated in the initialization of the humoral immune response, in the context of intradermal (i.d.) vaccination with particle-based antigens. In examining the spatial and temporal distribution of synthetic PLA particles adsorbed with the HIV-p24 protein, we observed their uptake by both cutaneous DCs and also skin-draining lymph node (dLNs) resident DCs. However, our immune response study highlighted that only skin cells, and in particular LCs, were able to stimulate polarization of follicular helper T cells (TFH) and the development of IgA-secreting B lymphocytes. I.d. vaccination also induced an inflammatory cell infiltration at both the injection site and in dLNs. Using a Ccr2-/- mouse model, we have shown the CCR2+ dependant cells can interfere in TFH polarization. Finally, the study of the dLN micro-environment suggested TNF can promote TFH formation. In conclusion, these findings highlight the importance of targeting skin DC in vaccination to propose new vaccine strategies
El, Sayed Rania. "ROLE OF FDCs AND FDC ACTIVATION IN PROMOTING HUMORAL IMMUNITY INCLUDING RESPONSES TO T-DEPENDENT ANTIGENS IN THE ABSENCE OF T CELLS." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1927.
Maho, Maud. "Evaluation des effets des traitements par Rituximab versus corticothérapie seule sur la réponse auto-réactive des patients atteints de pemphigus. First-line Rituximab combined with short-term Prednisone versus Prednisone alone for the treatment of Pemphigus (RITUX 3) : a prospective, multicentre, parallel-group, open-label randomised trial Risk factors for short-term relapse in patients with pemphigus treated by Rituximab as first-line therapy Rituximab and corticosteroid effect on Desmoglein specific B cells and T follicular helper cells in patients with Pemphigus Modifications or the transcriptomic profile of autoreactive B cells from pemphigus patients after treatment with Rituximab or standard corticosteroid regimen Long-term increase of Kcnn4 potassium channel surface expression on B cells in pemphigus patients after Rituximab treatment Rituximab is an effective treatment in patients with Pemphigus Vulgaris and demonstrates a steroid-sparing effect Modifications of the BAFF/BAFF-Receptor axis in patients with pemphigus treated with rituximab versus standard corticosteroids regimen. CD11C+ B cells are mainly memory cells prone to differentiate into antibody-secreting cells." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR132.
Pemphigus is an autoimmune disease of the skin and mucous membranes caused by autoantibodies (Ab) specific to desmoglein (Dsg) 1 or 3. These pathogenic Ab inhibit cell adhesion of keratinocytes. The development of pemphigus is associated with the conjunction of many uncommon events involving the emergence and then the cooperation of auto-reactive B cells and T cells link to genetic and environmental factors. Until now, the first line of treatment consisted of high doses of corticosteroids. Rituximab (RTX), an anti-CD20 chimeric monoclonal antibody, is an innovative therapy that results in B cells depletion. The RITUX 3 clinical trial was designed to evaluate the efficacy and safety of RTX combined with a short-course glucocorticoid therapy as a first-line treatment of pemphigus versus the standard treatment with standard corticosteroids (CS). As a first step, our clinico-biological analysis of patients after 24 months has shown that the use of RTX combined with short-term prednisone as a first-line treatment in patients with moderate to severe pemphigus is both more effective and better tolerated than the reference treatment with prednisone alone. Respectively, 89% of patients versus 34% in each group and both pemphigus foliaceus and pemphigus vulgaris patients responded. This efficacy was confirmed in the longer term after reconstitution of the B lymphocyte repertoire with a risk of relapse of only 2% at 36 months. The presence of a severe form of pemphigus at diagnosis (PDAI ≥ 45) and an anti-Dsg Ab level at 3 months above threshold values (anti-DSG1 ≥ 20 or anti-DSG3 ≥ 120) are associated with 50% risk of early relapse. These two predictive factors make it possible to identify a subgroup of patients at high risk of relapse requiring a maintenance infusion of RTX at the 6th month. In a second step, we studied the impact of RTX and CS treatments in patients with pemphigus in order to better understand the autoimmune response. The phenotypic characterization of auto-reactive B cells and the analysis of the frequency of B cells able of secreting anti-Dsg immunoglobulin (Ig) G by an ELISPOT approach demonstrated that the efficacy of RTX treatment in pemphigus seems related to the elimination of IgG-switched Dsg memory B-cells. Dsg specific B cells remain detectable after RTX when B cells return, but these B cells have a naïve and non-switched (IgM) phenotype and no longer secrete IgG. On the other hand, the persistence of self-reactive Dsg B cells capable of secreting IgG anti-Dsg after treatment with CS is certainly at the origin of the frequency of relapses. The unicellular targeted gene expression analysis demonstrated that initially, Dsg-specific B cells have a pro-inflammatory profile with the overexpression of three genes encoding Interleukin (IL) -1β, IL-12p35 and IL-23p19 and for the IRF5 gene (Interferon regulatory factor 5) compared to non-self-reactive B cells. RTX and CS have different effects on the expression of these genes, but both reduce the gene expression of IL-1β, which seems to play an important role in the pathophysiology of pemphigus
Gong, Ya-Zhuo. "Role of salivary gland epithelial cells in the differentiation and activation of T lymphocytes in primary Sjögren's syndrome." Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ100/document.
The primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by dry mouth and dry eyes. Salivary gland epithelial cells (SGECs) of patients with pSS express the molecules involved in immune responses and act as antigen presenting cells. Follicular helper T cells (Tfh) secrete IL-21 whose augmented secretion is a hallmark of several autoimmunediseases. Here we investigated whether SGECs were capable to induce Tfh differentiation. We report that IL-6 and ICOSL expression by SGECs contributes to naïve CD4+ T differentiation into Tfh cells, as evidenced by their acquisition of a specific phenotype, characterized by Bcl-6, ICOS and CXCR5 expression and IL-21 secretion, but also but by their main functional feature: the capacity to enhance B lymphocytes survival. OX40/OX40L interaction is a pivotal costimulatory pathway. Polymorphisms of OX40L are involved in the genetic predisposition to pSS. We therefore investigated the pathogenic role of OX40/OX40L pathway in pSS. We demonstrated that the proportion of circulating CD4+ T cells expressing OX40 was elevated in patients with pSS and correlated with systemic disease activity. In salivary glands of patients with pSS, epithelial cells overexpressed OX40L and the expression of OX40L and OX40 was respectively evidenced on infiltrating B and T cells. Coculture of T cells with SGECs increased the expression of OX40 by CD4+ T cells promoted T cell survival and proliferation through OX40/OX40L interaction. These studies demonstrate emphasizes unknown pathogenic roles of SGECs and suggests that Tfh, IL-21 and OX40L might be therapeutic targets in pSS
Le, saos-Patrinos Corentin. "Rôle des lymphocytes T CD4+ folliculaires dans la physiopathologie de la leucémie lymphoïde chronique." Electronic Thesis or Diss., Bordeaux, 2022. http://www.theses.fr/2022BORD0093.
Chronic lymphocytic leukemia (CLL), one of the most common adult leukemia, is associated with variable outcomes, ranging from patients who have a stable disease with a nearly normal life expectancy to patients with a progressive disease and severe complications that ultimately lead to a poor survival. CLL is defined by the accumulation and proliferation of mature CD5+ B-lymphocytes in the bone marrow, peripheral lymphoid organs and blood. Although genetic alterations play a key role in CLL pathogenesis and support malignant transformation of B cells, multiple studies have demonstrated that interactions of CLL B cells (B-CLL) with accessory cells are essential for B-CLL proliferation and promote their resistance to apoptosis. Particularly, B-CLL follow chemokine gradients into lymph nodes (LN) where they organize into proliferation centers in which they encounter activated T cells, which further support their growth by increasing their resistance to apoptosis. Moreover, adoptive transfer of autologous CD4+ T cells into mice was demonstrated to promote B-CLL survival and proliferation in vivo highlighting the key role of T cells in B-CLL pathogenesis. Different CD4+ T cell subsets coexist, with each having their own phenotype and functions. Despite numerous studies addressing the role of T helper (Th) cells in CLL, the implication of each individual CD4+ T cell subset in CLL pathogenesis is still under debate. As an example, large amount of IFNγ were detected in the plasma of CLL-bearing animals, suggesting a role of Th1. Conversely, CLL progression in a genetic mouse model of the disease was reported to be independent of Th1 cells. In addition to multiple studies using either patient samples or mouse models of CLL have implicated Th2/Th9 CD4+ T cell subsets in disease progression as well. The conflicting results regarding CD4+ T helper subsets involved in CLL pathogenesis might be due to studies performed in different mouse models of the disease and using patient samples from different disease stages. Therefore, we thus performed an unsupervised study by flow cytometry on peripheral blood from control individuals and untreated CLL patients to get snapshots of the T cell compartment across the disease spectrum. Our results showed an increase in the CXCR5+ T follicular helper cells (Tfh) population, a subset playing a critical role in mediating the selection, survival and differentiation of B cells into antibody secreting cells and memory B cells through the expression of CD40L and IL-21 production. Importantly Tfh from CLL patient were skewed toward an activated Th1-profile as evidenced by their PD1+IL-21+IFNγ+ phenotype. The highest accumulation of Tfh cells was observed in advanced stages of the disease and Th1-like Tfh levels inversely correlated with serum IgG and IgA levels, decreased Ig levels being a risk factor for infectious complications. We were also able to uncover a correlation between the number of Tfh cells and the tumor burden represented by the number of circulating malignant B cells. Finally, we showed that Tfh cells effectively induce B-CLL proliferation in an IL-21 dependent but IFNγ independent mechanism. Our data therefore support the involvement of Tfh cells in CLL disease course
Vaineau, Romain. "Impact of IL-1β on Tfh and Tfr lymphocytes during physiological and pathological germinal center reaction." Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS504.
T follicular helper (Tfh) and T follicular regulatory (Tfr) cells orchestrate the germinal center (GC) reaction by providing balance to B cell maturation. The harmonious interplay between Tfh, Tfr and B cells fosters high affinity antibody production, while its dysregulation can yield to autoimmunity, highlighting the importance of the underlying regulatory mechanisms. In this context, the role of Interleukin-1β (IL-1β) emerges as a focal interest. This proinflammatory cytokine is well-documented in modulating innate immune responses through the agonist receptor IL-1R1 while IL-1R2 exerts a decoy function by sequestering IL-1β. However, its specific interaction with Tfh and Tfr is not fully elucidated. This study embarks on a critical exploration of IL-1β's influence on the dynamic equilibrium of Tfh and Tfr, transcending the limitations of previous studies predominantly confined to murine models. Here, we carry an original systems immunology approach encompassing the use of varied human secondary lymphoid organs that embody distinct stages of Tfh and Tfr maturation. We reveal differential patterns of IL-1 receptors that govern Tfr heterogeneity, and trajectory inference predicts a bifurcation branching out from GC-Tfh. IL-1R1 expression is associated to Tfh maturation, and its excess over IL-1R2 precipitates the transition to a unique Tfr phenotype contrasting with the one described in mice. The application of single-cell RNA sequencing together with immunophenotyping confirmed Tfh and Tfr responsiveness to IL-1β, which promotes their functionality. A patient cohort suggested a tangible link between dysregulated IL-1β signaling and pronounced aberrancies in Tfh and Tfr responses during autoimmune pathogenesis. Collectively, our findings underscore IL-1β’s pivotal role in Tfh and Tfr cell dynamics through the interplay of IL-1 receptors, unveiling its influence on GC-mediated antibody responses. This study offers new insights into autoimmune disease mechanisms and potential interventions
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.
Atopic 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
Powell, Michael D. "Insights Into the Regulatory Requirements for T Follicular Helper Cell Development." Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/89085.
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.
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.
Recent 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
Levin, Clément. "Mécanismes moléculaires et cellulaires dans l’induction des réponses T helper folliculaires après vaccination cutanée." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066480/document.
Skin vaccination is of great interest, as it enables targeting of the antigen to unique and specialized dendritic cell populations of the skin, as well as recruitment of inflammatory blood cells.T follicular helper (TFH) cells play a critical role in the setting of the humoral response. However, the cellular and molecular interactions that underlie their induction after vaccination remain unknown.My thesis project aimed at understanding the immune mechanisms by which skin vaccination could favor the induction of TFH and humoral immune responses by studying the early events that take place in tissue and lymph node.Using mice models, we evaluated the relative contributions of various populations from the skin, lymph node and blood in the setting of TFH cell responses after intradermal immunization with nanoparticles coated with p24 antigen from HIV. This revealed a crucial role of Langerhans cells and skin migratory dendritic cells in the induction of TFH and germinal center responses.We then evaluated the ability of different adjuvant formulations to polarize the TFH and humoral response against a promising vaccine antigen from HIV envelope protein. Emulsifying the antigen in IFA favors the induction of TFH cells and induces the production of neutralizing antibodies able to block viral infection.This work highlights the relevance of targeting skin dendritic cells by using relevant vaccination routes and adjuvant formulation able to induce TFH cell responses
Bin, Sofia <1990>. "Erythropoietin reduces pathogenic humoral immunity by inhibiting T Follicular Helper cell differentiation and function." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2021. http://amsdottorato.unibo.it/9694/1/TesiPhD_SofiaBin_Final.pdf.
Boyden, Alexander Wiser. "Influenza A virus induces regulated T cell-driven B cell responses." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/3432.
Suhail, Tahir. "A CD153+ CD4+ T follicular cell population with cell-senescence features plays a crucial role in lupus pathogenesis via osteopontin production." Kyoto University, 2015. http://hdl.handle.net/2433/202671.
Rydyznski, Carolyn E. "Natural Killer Cell Regulation of Humoral Immunity." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535377157934852.
Wang, Ling, Dechao Cao, Ling Wang, Juan Zhao, Lam Nhat Nguyen, Xindi Dang, Yingjie Ji, et al. "HCV-associated Exosomes Promote Myeloid-Derived Suppressor Cell Expansion via Inhibiting miR-124 to Regulate T Follicular Cell Differentiation and Function." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etsu-works/6524.