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Chromatin accessibility landscapes of CX3CR1+ effector , CX3CR1- Ly108- exhausted, or Ly108+ progenitor CD8 T cells during chronic viral infection.

ABSTRACT: During chronic viral infection, pathogen-specifc CD8+ T cells develop into three main phenotypically and functionally distinct subsets: TCF1hi progenitor, PD-1hi exhausted, and recently identied CX3CR1+ cytotoxic effector cells. Although genetic programs governing progenitor and exhausted subset formation have been well-studied, how CX3CR1+ effector CD8+ T cell differentiation is transcriptionally and epigentically regulated remains elusive. In this study, our single cell transcriptomics and epigenetic assays revealed that three subsets of virus-specific cells were governed by distinct gene regulatory networks (GRNs) and epigenetic landscapes. Computational analyses demonstrated a striking similarity between the CX3CR1+ subset and short-live effector cells (SLECs) from acute LCMV infection. Consistently, genetic deletion of T-bet (Tbx21) significantly diminished the formation and function of the CX3CR1+ subset. Importantly, we identify that the transcription factor (TF) BATF is required to maintain a permissive chromatin structure that allows differentiation transition from TCF1+ progenitor to CX3CR1+ effector cells. Intriguingly, haplodificiency of BATF in CD8+ T cells abolished CX3CR1+ effector subset formation. Lastly, we found that BATF directly bound to key genetic regions such as Tbx21 and modulated their enhancer accessibility to facilitate progenitor to CX3CR1+ effector cell transition. These mechanistic insights can be harnessed to overcome T cell exhaustion in treating chronic infections and cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE149752 | GEO | 2021/05/22

REPOSITORIES: GEO

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Genome-wide maps of histone modifications in CX3CR1+ effector , CX3CR1- Ly108- exhausted, or Ly108+ progenitor CD8 T cells during chronic viral infection.

Project description:During chronic viral infection, pathogen-specifc CD8+ T cells develop into three main phenotypically and functionally distinct subsets: TCF1hi progenitor, PD-1hi exhausted, and recently identied CX3CR1+ cytotoxic effector cells. Although genetic programs governing progenitor and exhausted subset formation have been well-studied, how CX3CR1+ effector CD8+ T cell differentiation is transcriptionally and epigentically regulated remains elusive. In this study, our single cell transcriptomics and epigenetic assays revealed that three subsets of virus-specific cells were governed by distinct gene regulatory networks (GRNs) and epigenetic landscapes. Computational analyses demonstrated a striking similarity between the CX3CR1+ subset and short-live effector cells (SLECs) from acute LCMV infection. Consistently, genetic deletion of T-bet (Tbx21) significantly diminished the formation and function of the CX3CR1+ subset. Importantly, we identify that the transcription factor (TF) BATF is required to maintain a permissive chromatin structure that allows differentiation transition from TCF1+ progenitor to CX3CR1+ effector cells. Intriguingly, haplodificiency of BATF in CD8+ T cells abolished CX3CR1+ effector subset formation. Lastly, we found that BATF directly bound to key genetic regions such as Tbx21 and modulated their enhancer accessibility to facilitate progenitor to CX3CR1+ effector cell transition. These mechanistic insights can be harnessed to overcome T cell exhaustion in treating chronic infections and cancer.

2021-05-22 | GSE149810 | GEO

CUT&Tag ChIP-seq analysis of BATF in CX3CR1+ effector , CX3CR1- Ly108- exhausted, or Ly108+ progenitor CD8 T cells during chronic viral infection.

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Identification of a T-bet hi Quiescent Exhausted CD8 T Cell Subpopulation That Can Differentiate into TIM3 + CX3CR1 + Effectors and Memory-like Cells

Project description:Persistent Ag induces a dysfunctional CD8 T cell state known as "exhaustion" characterized by PD-1 expression. Nevertheless, exhausted CD8 T cells retain functionality through continued differentiation of progenitor into effector cells. However, it remains ill-defined how CD8 T cell effector responses are sustained in situ. In this study, we show using the mouse chronic lymphocytic choriomeningitis virus infection model that CX3CR1+ CD8 T cells contain a T-bet-dependent TIM3-PD-1lo subpopulation that is distinct from the TIM3+CX3CR1+PD-1+ proliferative effector subset. The TIM3-CX3CR1+ cells are quiescent and express a low but significant level of the transcription factor TCF-1, demonstrating similarity to TCF-1hi progenitor CD8 T cells. Furthermore, following the resolution of lymphocytic choriomeningitis virus viremia, a substantial proportion of TCF-1+ memory-like CD8 T cells show evidence of CX3CR1 expression during the chronic phase of the infection. Our results suggest a subset of the CX3CR1+ exhausted population demonstrates progenitor-like features that support the generation of the CX3CR1+ effector pool from the TCF-1hi progenitors and contribute to the memory-like pool following the resolution of viremia.

2021-04-13 | GSE148497 | GEO

CUT&Tag ChIP-seq analysis of BATF in CX3CR1+ effector , CX3CR1- Ly108- exhausted, or Ly108+ progenitor CD8 T cells during chronic viral infection.

Project description:CUT&Tag ChIP-seq analysis of BATF in CX3CR1+ effector , CX3CR1- Ly108- exhausted, or Ly108+ progenitor CD8 T cells during chronic viral infection.

| PRJNA630193 | ENA

Chromatin accessibility landscapes of CX3CR1+ effector , CX3CR1- Ly108- exhausted, or Ly108+ progenitor CD8 T cells during chronic viral infection.

Project description:Chromatin accessibility landscapes of CX3CR1+ effector , CX3CR1- Ly108- exhausted, or Ly108+ progenitor CD8 T cells during chronic viral infection.

| PRJNA630086 | ENA

Genome-wide maps of histone modifications in CX3CR1+ effector , CX3CR1- Ly108- exhausted, or Ly108+ progenitor CD8 T cells during chronic viral infection.

Project description:Genome-wide maps of histone modifications in CX3CR1+ effector , CX3CR1- Ly108- exhausted, or Ly108+ progenitor CD8 T cells during chronic viral infection.

| PRJNA630212 | ENA

STAT3 regulates CD8+ T cell differentiation and functions in cancer [ChIP-seq]

Project description:In cancer, persistent antigens drive CD8+ T cell differentiation into exhausted progenitor (Texprog) and terminally exhausted (Texterm) cells. However, how the extrinsic and intrinsic regulatory mechanisms cooperate during this process still remain not well understood. Here, we found STAT3 signaling plays essential roles in promoting intra-tumor Texterm cell development, by enhancing their effector functions and survival, which results in better tumor control. In tumor microenvironments, STAT3 is predominantly activated by IL-10 and IL-21, but not IL-6. Besides, STAT3 also plays critical roles in the development and function of terminally differentiated effector CD8+ T cells in acute infection. Mechanistically, STAT3 transcriptionally promotes the expression of effector function-related genes, while suppresses those expressed by progenitor Tex subset. Moreover, STAT3 functions in collaboration with BATF and IRF4 to mediate chromatin activation at effector gene loci. Thus, we have elucidated the roles of STAT3 signaling in terminally differentiated CD8+ T cell development, especially in cancer, which benefits developing more effective immunotherapies against tumor.

2022-12-25 | GSE217374 | GEO

STAT3 regulates CD8+ T cell differentiation and functions in cancer [ATAC-seq]

2022-12-25 | GSE217372 | GEO

STAT3 regulates CD8+ T cell differentiation and functions in cancer [RNA-seq]

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CX3CR1/Fractalkine receptor expression separates memory CD8+ T cells with distinct functional profiles (expression)

Project description:Memory T cells are important for protective immunity against infectious microorganisms. Such protection is achieved by cooperative action of memory T cell populations that differ in their tissue localization and functionality. We report on the identification of the fractalkine receptor CX3CR1 as marker for stratification of memory T cells with cytotoxic effector function from those with proliferative function in both, mice and man. Based on CX3CR1 and CD62L expression levels four distinct memory T cell populations can be distinguished based on their functional properties. Transcriptome and proteome profiling revealed that CX3CR1 expression was superior to CD62L to resolve memory T cell functionality and allowed determination of a core signature of memory T cells with cytotoxic effector function. This identifies a CD62Lhi CX3CR1+ memory T cell population with an identical gene signature to CD62LlowCX3CR1+ effector memory T cells. In lymph nodes, this so far unrecognized CD62LhiCX3CR1+ T cell population shows a distinct migration pattern and anatomic positioning compared to CD62LhiCX3CR1neg TCM. Furthermore, CX3CR1+ memory T cells were scarce or absent during chronic HBV, HCV and HIV infection in man and chronic LCMV infection in mice confirming the value of CX3CR1+ in understanding principles of protective immune memory. CD8+ T cells were isolated and directly assessed or incubated with DC or LSEC. After harvesting, cells were immediately lysed in Trizol (Invitrogen) before storage at -80Â°C for RNA isolation.

2016-06-10 | E-GEOD-63118 | biostudies-arrayexpress

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