CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance
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ABSTRACT:
PROVIDER: PRJNA562906 | ENA |
REPOSITORIES: ENA
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Project description:Follicular T-helper (TFH) cells highly express the programmed cell death-1 (PD-1) molecule. Whereas inhibition of T cell receptor (TCR) signaling and CD28 co-stimulation is thought to be the primary mode of PD-1 functions, how PD-1 regulates TFH development and function remains unclear. Here we show that, when engaged by the ensemble of bystander B cells constitutively expressing PD-1 ligand 1 (PD-L1), PD-1 inhibits T-cell recruitment into follicles. This inhibition involves suppression of PI3K activities downstream of follicle-guidance receptor CXCR5, is independent from co-signaling with the TCR, and necessitates ICOS signaling to overcome. PD-1 further restricts CXCR3 upregulation on TFH cells, serving to concentrate these cells toward the GC territory, where PD-L1-PD-1 interactions between individual TFH and B cells optimize B-cell competition and affinity maturation. Therefore, operating in both costimulation-independent and -dependent manners, PD-1 plays an integral role in orchestrating tissue positioning and function of TFH cells.
2018-08-30 | GSE112066 | GEO
Project description:T follicular helper cells (TFH) are heterogenic population of CD4+ T cells, expressing CXCR5+ and PD-1+ on their surface. Their role is linked to supporting formation of germinal centres (GC) and these cells are thought to express high levels of PD-1 marker. Two models of immunisation were used to investigate the role of PD-1 low TFH. In Salmonella enterica infection high frequency of T follicular helper cells expressing low levels of PD-1 surface molecule are observed within first week of infection but GC do not appear until much a later stage (week 7-8). Sheep red blood cell immunisation (SRBC) gives rise to both TFH and GC B cells within first week of response and these TFH express low to high level of PD-1 molecule. Microarray analysis was applied in order to investigate the relationship between and characteristics of different TFH populations in order to elucidate their role in GC support, developmental stage and contributions to memory T cell pool.
2015-12-25 | GSE62961 | GEO
Project description:The vast majority of currently licensed human vaccines work on the basis of long-term protective antibody responses. Generation of long term humoral immunity is a complex process predominantly dependent on germinal centers and CD4 T cell help to B cells. Follicular helper T cells (Tfh) are the specialized CD4 T cells for B cell help. However, whether such cells develop memory in humans and can be tracked in human blood has been enigmatic. We identified a subpopulation of blood CXCR5+ PD-1+CXCR3- resting CD4 T cells that are most related to Tfh cells of lymphoid tissue by gene expression profile and phenotype. Functional analysis showed that these memory Tfh cells were specialized for helping B cells. Moreover, these cells correlate with a clinically important outcome: development of potent neutralizing antibodies against HIV in HIV+ individuals. CD4 T cells were enriched from fresh blood of 5 normal donors by magnetic beads negative selection. Following enrichment, CD14-CD16-CD19-CD8-CD4+CD45RA- cells from each donor were FACS sorted into the following 5 populations: CXCR5-, CXCR5+PD1+CXCR3-, CXCR5+PD1+CXCR3+, CXCR5+PD1-CXCR3-, and CXCR5+PD1-CXCR3+. The gene expression profile of each cell population was determined.
2013-11-12 | E-GEOD-50390 | biostudies-arrayexpress
Project description:CD4 T cell help is critical for both the generation and maintenance of germinal centers, and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. SAP (SH2D1A) expression in CD4 T cells is essential for germinal center development. However, SAP-deficient mice have only a moderate defect in TFH differentiation as defined by common TFH surface markers. CXCR5+ TFH cells are found within the germinal center as well as along the boundary regions of T/B cell zones. Here we show that germinal center associated T cells (GC TFH) can be identified by their co-expression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. Here we show GC TFH are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH subset and SAP- TFH are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that utilizes SAP signaling, is specifically required for IL-4 production by GC TFH. GC TFH cells require IL-4 and IL-21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by germinal center CD4 T cells but not in TFH and GC TFH differentiation. Analysis of in vivo antigen-specific (LCMV-specific, SMARTA TCR transgenic) WT and Sh2d1a-/- follicular helper CD4 T cells (CXCR5high),versus non-follicular helper CD4 T cells (CXCR5low), eight days after viral infection.
2010-04-28 | E-GEOD-21379 | biostudies-arrayexpress
Project description:T follicular helper CD4 T cells (Tfh) provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of CXCR5+ and PD-1+ cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike blood, we consistently identified a CXCR5-Bright PD-1-Bright (CXCR5BrPD-1Br) Tfh population in thoracic duct lymph (TDL). These CXCR5BrPD-1Br TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5BrPD-1Br TDL Tfh, and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the CXCR5BrPD-1Br TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue.
2019-07-01 | GSE130791 | GEO
Project description:T follicular helper CD4 T cells (Tfh) provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of CXCR5+ and PD-1+ cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike blood, we consistently identified a CXCR5-Bright PD-1-Bright (CXCR5BrPD-1Br) Tfh population in thoracic duct lymph (TDL). These CXCR5BrPD-1Br TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5BrPD-1Br TDL Tfh, and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the CXCR5BrPD-1Br TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue.
2019-07-01 | GSE130793 | GEO
Project description:We demonstrate that CXCR5+CD8+ T cells are a distinct human T-cell subset that homes to follicles and exerts strong antitumor activity compared with CXCR5-CD8+ T cells. Importantly, this subset is associated with improved outcome in follicular lymphoma patients.
2020-09-02 | GSE105095 | GEO
Project description:Analysis of in vivo antigen-specific (LCMV-specific, SMARTA TCR transgenic) follicular helper CD4 T cells (CXCR5high),versus non-follicular helper CD4 T cells (CXCR5low), eight days after viral infection. A paper including data analysis of these experiments has been accepted for publication (Robert J. Johnston et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of follicular helper CD4 T cell differentiation). Experiment Overall Design: Analysis of in vivo antigen-specific (LCMV-specific, SMARTA TCR transgenic) follicular helper CD4 T cells (CXCR5high), versus non-follicular helper CD4 T cells (CXCR5low), eight days after viral infection.
2009-08-07 | E-GEOD-16697 | biostudies-arrayexpress
Project description:In response to infection, antigen-specific CD8+ T cells are primed in the T cell zone of secondary lymphoid organs and differentiate into cytotoxic effector T (TC) cells. Concurrently, CD4+ T cells differentiate into follicular helper T (TFH) cells that localize to B cell follicles and promote protective antibody responses. During unresolved infections, however, some viruses including human immunodeficiency virus (HIV) or Epsteinâ??Barr virus (EBV) escape immune control and persist in TFH cells and B cells, respectively. Exclusion of Tc cells from B cell follicles is thought to be a major mechanism of immune evasion. New strategies are therefore needed to eradicate infected cells in follicles for a permanent cure. Using mouse infection models and human samples, we here identify a specialized group of TC cells expressing the chemokine receptor CXCR5 that can selectively enter B cell follicles and eradicate infected TFH and B cells. We demonstrate that differentiation of these cells, which we term follicular cytotoxic T (TFC) cells, requires the transcription factors Bcl6, E2A and Tcf1, whereas the transcriptional regulators Blimp1, Id3 and Id2 inhibit their development. We demonstrate that Blimp1 and E2A directly regulate Cxcr5 expression, and together with Bcl6 and Tcf1 form a transcriptional circuit that guides the TFC differentiation. The identification of a follicular subset of TC cells has far reaching implications for developing better strategies for the control of infections that target B cells and TFH cells and for the eradication of B cell derived malignancies. There is no associated input. The E2A Bio-ChIP-seq was performed with total thymocytes from Tcf3Bio/Bio Rosa26BirA/BirA mice
2016-08-01 | E-GEOD-84974 | biostudies-arrayexpress
Project description:Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.
| S-EPMC6765049 | biostudies-literature