Dependence on Bcl6 and Blimp1 identifies distinct mechanisms driving memory and follicular helper CD4+ T cell differentiation [scRNA-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE184847 | GEO | 2021/11/14
REPOSITORIES: GEO
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Project description:During the immune response, CD4+ T cells differentiate into distinct effector subtypes, including follicular helper T (Tfh) cells that help B cells, and into memory cells. Tfh and memory cells are required for long-term immunity; both depend on the transcription factor Bcl6, raising the question of whether they differentiate through similar mechanisms. Here, using notably single-cell RNA and ATAC sequencing, we show that virus-responding CD4+ T cells lacking both Bcl6 and Blimp1 can differentiate into cells with transcriptomic, chromatin accessibility and function attributes of memory cells, but not of Tfh cells. Thus, Bcl6 promotes memory cell differentiation primarily through its repression of Blimp1. These findings demonstrate that distinct mechanisms underpin the differentiation of memory and Tfh CD4+ cell and define the Bcl6-Blimp1 axis as a potential target for promoting long-term memory T cell differentiation.
2021-11-14 | GSE184846 | GEO
Project description:CD4+ T follicular helper (Tfh) cells are essential for germinal center (GC) and high-affinity antibody responses. Yet the regulation that determines the initial development of Tfh cells is still largely unknown. Here we find that transcription factor Foxp1, previously shown to be essential in maintaining T cell quiescence, is a rate-limiting and essential negative regulator of Tfh cell differentiation. NaM-CM-/ve CD4+ T cells constitutively express Foxp1A, and stimulation through the T cell receptor (TCR) transiently induces the expression of a shorter Foxp1D isoform. In T cell-dependent (TD) humoral responses, CD4+ T cells deficient in all Foxp1 isoforms preferentially differentiate into Tfh cells, resulting in substantially increased GC and antibody responses. This negative regulation of Foxp1 on Tfh cell differentiation shows profound dominance: even in the absence of B cells, Foxp1-deficient CD4+ T cells differentiate into Tfh cells with high frequencies and sustained Bcl6 expression. Further, in the absence of Foxp1, Tfh cells are generated in higher frequencies than seen with Bcl6 overexpression and Tfh cell differentiation becomes significantly resistant to Blimp1-mediated repression. Finally, our experiments reveal specific roles of Foxp1A and Foxp1D in inhibiting Tfh cell differentiation: TCR-induced Foxp1D functions as a M-bM-^@M-^XgatekeeperM-bM-^@M-^Y to block the initial Tfh cell development, and together Foxp1A and Foxp1D proteins inversely determine Tfh cell generation in a dosage-dependent manner. Our study suggests that two Foxp1 isoforms provide a M-bM-^@M-^\double checkM-bM-^@M-^] mechanism as fundamental regulators in Tfh cell differentiation and humoral responses. Gene expression analysis of ex vivo OT-II Foxp1-WT Tfh cells and OT-II Foxp-conditional knockout (CKO) Tfh cells 5 days after immunization.
2014-05-18 | E-GEOD-50725 | 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:Following an infection, CD4+ lymphocytes can differentiate into long-lived memory T cells, some of which circulate through the secondary lymphoid organs (SLOs) while a population lodges in non-lymphoid tissues. While CD4+ T cells in SLOs have been examined, the developmental origins and transcriptional regulation of tissue-resident memory T cells (TRM) remain largely undefined. Here, we investigated the phenotypic, functional, and transcriptional profile of virus-specific CD4+ TRM in the small intestine (SI) following acute lymphocytic choriomeningitis virus (LCMV) infection. LCMV-specific CD4+ TRM at day 7 of infection shared a gene-expression program and chromatin profile with TH1 cells and progressively acquired a mature TRM program by day 21 memory time point, supporting a developmental relationship between TRM and TH1 subsets. Furthermore, we demonstrated that TRM cells expressed genes associated with both effector and memory T cell fates, including the transcriptional regulators Blimp1, Id2, and Bcl6 which were necessary for CD4+ TRM differentiation. TH1-associated Blimp1 and Id2 were both required for early TRM formation, while TFH-associated Bcl6 initially inhibited TRM differentiation but was critical for development of long-lived TRM cells. Our results identify new significance for TFs previously associated with circulating CD4+ T cell populations and their roles in driving SI CD4+ TRM differentiation.
2023-06-30 | GSE184260 | GEO
Project description:Following an infection, CD4+ lymphocytes can differentiate into long-lived memory T cells, some of which circulate through the secondary lymphoid organs (SLOs) while a population lodges in non-lymphoid tissues. While CD4+ T cells in SLOs have been examined, the developmental origins and transcriptional regulation of tissue-resident memory T cells (TRM) remain largely undefined. Here, we investigated the phenotypic, functional, and transcriptional profile of virus-specific CD4+ TRM in the small intestine (SI) following acute lymphocytic choriomeningitis virus (LCMV) infection. LCMV-specific CD4+ TRM at day 7 of infection shared a gene-expression program and chromatin profile with TH1 cells and progressively acquired a mature TRM program by day 21 memory time point, supporting a developmental relationship between TRM and TH1 subsets. Furthermore, we demonstrated that TRM cells expressed genes associated with both effector and memory T cell fates, including the transcriptional regulators Blimp1, Id2, and Bcl6 which were necessary for CD4+ TRM differentiation. TH1-associated Blimp1 and Id2 were both required for early TRM formation, while TFH-associated Bcl6 initially inhibited TRM differentiation but was critical for development of long-lived TRM cells. Our results identify new significance for TFs previously associated with circulating CD4+ T cell populations and their roles in driving SI CD4+ TRM differentiation.
2023-06-30 | GSE184259 | GEO
Project description:Following an infection, CD4+ lymphocytes can differentiate into long-lived memory T cells, some of which circulate through the secondary lymphoid organs (SLOs) while a population lodges in non-lymphoid tissues. While CD4+ T cells in SLOs have been examined, the developmental origins and transcriptional regulation of tissue-resident memory T cells (TRM) remain largely undefined. Here, we investigated the phenotypic, functional, and transcriptional profile of virus-specific CD4+ TRM in the small intestine (SI) following acute lymphocytic choriomeningitis virus (LCMV) infection. LCMV-specific CD4+ TRM at day 7 of infection shared a gene-expression program and chromatin profile with TH1 cells and progressively acquired a mature TRM program by day 21 memory time point, supporting a developmental relationship between TRM and TH1 subsets. Furthermore, we demonstrated that TRM cells expressed genes associated with both effector and memory T cell fates, including the transcriptional regulators Blimp1, Id2, and Bcl6 which were necessary for CD4+ TRM differentiation. TH1-associated Blimp1 and Id2 were both required for early TRM formation, while TFH-associated Bcl6 initially inhibited TRM differentiation but was critical for development of long-lived TRM cells. Our results identify new significance for TFs previously associated with circulating CD4+ T cell populations and their roles in driving SI CD4+ TRM differentiation.
2023-06-30 | GSE184252 | GEO
Project description:Following an infection, CD4+ lymphocytes can differentiate into long-lived memory T cells, some of which circulate through the secondary lymphoid organs (SLOs) while a population lodges in non-lymphoid tissues. While CD4+ T cells in SLOs have been examined, the developmental origins and transcriptional regulation of tissue-resident memory T cells (TRM) remain largely undefined. Here, we investigated the phenotypic, functional, and transcriptional profile of virus-specific CD4+ TRM in the small intestine (SI) following acute lymphocytic choriomeningitis virus (LCMV) infection. LCMV-specific CD4+ TRM at day 7 of infection shared a gene-expression program and chromatin profile with TH1 cells and progressively acquired a mature TRM program by day 21 memory time point, supporting a developmental relationship between TRM and TH1 subsets. Furthermore, we demonstrated that TRM cells expressed genes associated with both effector and memory T cell fates, including the transcriptional regulators Blimp1, Id2, and Bcl6 which were necessary for CD4+ TRM differentiation. TH1-associated Blimp1 and Id2 were both required for early TRM formation, while TFH-associated Bcl6 initially inhibited TRM differentiation but was critical for development of long-lived TRM cells. Our results identify new significance for TFs previously associated with circulating CD4+ T cell populations and their roles in driving SI CD4+ TRM differentiation.
2023-06-30 | GSE184262 | GEO
Project description:CD4+ T follicular helper (Tfh) cells are essential for germinal center (GC) and high-affinity antibody responses. Yet the regulation that determines the initial development of Tfh cells is still largely unknown. Here we find that transcription factor Foxp1, previously shown to be essential in maintaining T cell quiescence, is a rate-limiting and essential negative regulator of Tfh cell differentiation. Naïve CD4+ T cells constitutively express Foxp1A, and stimulation through the T cell receptor (TCR) transiently induces the expression of a shorter Foxp1D isoform. In T cell-dependent (TD) humoral responses, CD4+ T cells deficient in all Foxp1 isoforms preferentially differentiate into Tfh cells, resulting in substantially increased GC and antibody responses. This negative regulation of Foxp1 on Tfh cell differentiation shows profound dominance: even in the absence of B cells, Foxp1-deficient CD4+ T cells differentiate into Tfh cells with high frequencies and sustained Bcl6 expression. Further, in the absence of Foxp1, Tfh cells are generated in higher frequencies than seen with Bcl6 overexpression and Tfh cell differentiation becomes significantly resistant to Blimp1-mediated repression. Finally, our experiments reveal specific roles of Foxp1A and Foxp1D in inhibiting Tfh cell differentiation: TCR-induced Foxp1D functions as a ‘gatekeeper’ to block the initial Tfh cell development, and together Foxp1A and Foxp1D proteins inversely determine Tfh cell generation in a dosage-dependent manner. Our study suggests that two Foxp1 isoforms provide a “double check” mechanism as fundamental regulators in Tfh cell differentiation and humoral responses.
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Project description:Population gene expression of effector CD4+ T cells WT, Bcl6-deficient , Blimp1-deficient or Bcl6 Blimp1-deficient was determined by RNAseq after LCMV Armstrong infection
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Project description:Single-cell gene expression of effector CD4+ T cells WT, Bcl6-deficient , Blimp1-deficient or Bcl6 Blimp1-deficient was determined by scRNAseq after LCMV Armstrong infection
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