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Cish inhibits CD8+ T cell immunity and disrupts proximal T cell receptor signaling

ABSTRACT: T cell receptor (TCR) signaling is a critical process in immunity to infectious disease and cancer. Recently, a genome-wide association study has implicated polymorphisms in the CISH locus with susceptibility to infectious diseases. However, the role of Cish in the immune responses and its molecular underpinnings remains unclear. Here we demonstrate that Cish deletion resulted in protection against viral infection and enhanced CD8+ T cell tumor immunity. Transcriptome profiling revealed a hyper-TCR activation signature in Cish-deficient CD8+ T cells. Subsequent analysis revealed an inhibitory role for Cish in PLCγ1 activation, ensuing Ca2+ release and downstream signaling. In the steady-state Cish was found to physically interact with PLCγ1, however, PLCγ1 was only found to be ubiquitinated after acute TCR stimulation in the presence of Cish. These data implicate Cish as a potent negative regulator of TCR signaling and T cell immunity to infection and cancer and may have significant clinical applications.

ORGANISM(S): Mus musculus

PROVIDER: GSE56328 | GEO | 2015/04/30

SECONDARY ACCESSION(S): PRJNA242918

REPOSITORIES: GEO

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Cish inhibits CD8+ T cell immunity and disrupts proximal T cell receptor signaling

Project description:T cell receptor (TCR) signaling is a critical process in immunity to infectious disease and cancer. Recently, a genome-wide association study has implicated polymorphisms in the CISH locus with susceptibility to infectious diseases. However, the role of Cish in the immune responses and its molecular underpinnings remains unclear. Here we demonstrate that Cish deletion resulted in protection against viral infection and enhanced CD8+ T cell tumor immunity. Transcriptome profiling revealed a hyper-TCR activation signature in Cish-deficient CD8+ T cells. Subsequent analysis revealed an inhibitory role for Cish in PLCγ1 activation, ensuing Ca2+ release and downstream signaling. In the steady-state Cish was found to physically interact with PLCγ1, however, PLCγ1 was only found to be ubiquitinated after acute TCR stimulation in the presence of Cish. These data implicate Cish as a potent negative regulator of TCR signaling and T cell immunity to infection and cancer and may have significant clinical applications. 4 biological replicates from wild-type mice and 3 biological replicates from Cish knock-out (-/-) mice were analyzed.

2015-04-30 | E-GEOD-56328 | biostudies-arrayexpress

Mus musculus

Project description:Cish inhibits CD8+ T cell immunity and disrupts proximal T cell receptor signaling

| PRJNA242918 | ENA

Recruitment of highly cytotoxic CD8+ T cell receptors in mild SARS-CoV-2 infection

Project description:T cell immunity is crucial for the control of SARS-CoV-2 infections and has been widely studied on a quantitative level. However, quality of responses, in particular of CD8+ T cells, has only been marginally investigated so far. Here, we isolated T cell receptor (TCR) repertoires specific for immunodominant SARS-CoV-2 epitopes restricted to common Human Leucocyte Antigen (HLA) class I molecules in convalescent individuals. SARS-CoV-2-specific CD8+ T cells were detected up to twelve months from infection. TCR repertoires were diverse, with heterogeneous functional avidity and cytotoxicity towards virus-infected cells, as demonstrated for TCR-engineered T cells. High TCR functionality correlated with gene signatures that, remarkably, could be retrieved for each epitope:HLA combination analyzed. Overall, our data demonstrate that polyclonal and highly functional CD8+ TCRs – classical features of protective immunity - are recruited upon mild SARS-CoV-2 infection, providing tools to assess the quality and to potentially restore functional CD8+ T cell immunity.

2022-01-07 | GSE190839 | GEO

Combined PD-L1/TGFb blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors

Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8 T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.

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BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers

Project description:T cell antigen receptor (TCR) signaling drives distinct responses depending upon the differentiation state and context of CD8+ T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity following viral infection. BACH2 was recruited to enhancers where it limited expression of TCR-driven genes by attenuating the availability of activator protein 1 (AP-1) sites to Jun family signal-dependent TFs. In naïve cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs.

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TGF-β and CIS inhibition overcomes NK cell suppression to restore anti-tumor immunity

Project description:Antibodies targeting “immune checkpoints” have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8 T cells. Interest in targeting analogous pathways in other cytotoxic lymphocytes is growing. Natural killer (NK) cells are key to cancer immunosurveillance by eradicating metastases and driving solid tumor inflammation. NK cell anti-tumor function is dependent on the cytokine interleukin (IL)-15. Ablation of the IL-15 signaling inhibitor CIS (Cish) enhances NK cell anti-tumor immunity by increasing NK cell metabolism and persistence within the tumor microenvironment (TME). The TME has also been shown to impair NK cell fitness via the production of immunosuppressive TGF-b, a suppression which occurs even in the presence of high IL-15 signaling. Here, we identified an unexpected interaction between CIS and the TGF-b signaling pathway in NK cells. Independently, Cish- and Tgfbr2- deficient NK cells are both hyper-responsive to IL-15 and hypo-responsive to TGF-b, with dramatically enhanced anti-tumor immunity. Remarkably, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development, suggesting that combining suppression of these two pathways might represent a novel therapeutic strategy to enhance innate anti-cancer immunity.

2022-04-11 | GSE200134 | GEO

Innate sensor Dhx9 orchestrates TCR signaling and controls CD8 T cell immunity against viral infection [ATAC-Seq]

Project description:Innate sensor Dhx9 orchestrates TCR signaling and controls CD8 T cell immunity against viral infection [ATAC-Seq]

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Direct regulation of T cell exhaustion by NFAT [ChIP-Seq]

Project description:During persistent antigen stimulation, CD8+ cytolytic T cells (CTL) show a gradual decrease in effector function, or “exhaustion”, which impairs the immune response to tumors and infections. Here we show that NFAT, a transcription factor with an established role in T cell activation, in parallel controls a second transcriptional program conferring the characteristic features of CD8+ T cell exhaustion, including upregulation of genes encoding inhibitory cell surface receptors and diminished TCR signaling. Expression of an engineered NFAT1, which induces this negative regulatory program in the absence of the effector program, interferes with the ability of CD8+ T cells to protect against Listeria infection or attenuate tumor growth in vivo. NFAT elicits this second program of gene expression in large part by binding to a subset of the sites occupied by NFAT during a typical effector response, suggesting that a balance between the two pathways determines the outcome of TCR signaling. Determination of NFAT1 binding sites in CD8 T cells in vitro

2015-02-13 | E-GEOD-64407 | biostudies-arrayexpress

Direct regulation of T cell exhaustion by NFAT [RNA-Seq]

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Cancer specific tissue-resident memory T cells expressed ZNF683 up-regulated by autocrine IFN-γin colorectal cancer

Project description:Tissue-resident memory T (Trm) cells express CD103 to be maintained in the local microenvironment and to be strongly involved in local immunity of epithelial tissue. Trm has been associated with cytotoxicity in pathologies of not only virus infection and autoimmune disease but also many cancers. Tumor infiltration by CD103+ Trm cells was associated with patient survival in colorectal cancer. Tumor infiltrating CD103+ Trm cells were comprised predominantly of CD8 T cells expressing cytotoxic activation and immune check-point molecules called exhausted markers. Therefore, we focused on ZNF683 as a marker of cancer-specific Trm. The expression of ZNF683 in Trm was up-regulated by TCR and IFN-γ signaling that was positive feedback by autocrine IFN-γ. These results indicate that IFN-γ and TCR signaling and ZNF683 are involved in the activation of Trm in tumor and would be promising targets for regulation of cancer immunity.

2022-03-25 | GSE188381 | GEO

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