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Follicular Regulatory T Cells Regulate the Development of Cytotoxic-like Follicular Helper T Cells

ABSTRACT: Follicular Regulatory T Cells Regulate the Development of Cytotoxic-like Follicular Helper T Cells

PROVIDER: PRJNA551695 | ENA |

REPOSITORIES: ENA

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Follicular Regulatory T Cells Regulate the Development of Cytotoxic-like Follicular Helper T Cells

Project description:T follicular regulatory (TFR) cells are found in the germinal center (GC) response and help shape the antibody (Ab) response. Whether TFR cells have a suppressive role, a helper role or both types of roles in the GC is unclear. Here, we addressed TFR cell function using 3 different strains of TFR cell mutant mice. After immunization, GC B cells but not T follicular helper (TFH) cell positively correlated with TFR cell levels. Using a gene profiling approach, we found that TFH cells from TFR-deficient mice showed strong up-regulation of granzyme B (Gzmb) and other effector CD8 T cell genes, many of which were Stat4 dependent. This aberrant cytotoxic T cell gene profile was increased in TFR-deficient mice crossed on a pro-inflammatory background. We detected Gzmb+ and Eomesodermin+ TFH cells and a higher rate of apoptotic GC B cells in the absence of TFR cells. Klrg1+ TFH cells expressed higher Gzmb and less IL-4 and IL-21. Our data show that TFR cells repress the development of abnormal cytotoxic TFH cells that correlate with a lower GC and Ab response. This data shows a novel mode of helper function for TFR cells in the GC response.

2019-06-29 | GSE133533 | GEO

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Transcription profiling of mouse vivo follicular helper CD4 T cells (TFH) versus non follicular helper CD4 T cells (non-TFH)

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CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles

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

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Expression Data from in vivo follicular helper CD4 T cells (TFH) versus non follicular helper CD4 T cells (non-TFH)

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Follicular Helper T Cells Progressively Differentiate to Regulate the Germinal Center Response

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Project description:IL-2 production defines precursors fated to become T Follicular Helper cells

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