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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. 4 biological replicates from wild-type mice and 3 biological replicates from Cish knock-out (-/-) mice were analyzed.

ORGANISM(S): Mus musculus

SUBMITTER: Shashank Patel

PROVIDER: E-GEOD-56328 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2015-04-30 | GSE56328 | GEO

Gene expression by antigen activated OT-I T cells in vivo in the presence and absence of IL-2

Project description:Much is known concerning the cellular and molecular basis for CD8+ T memory immune responses. Nevertheless, conditions that selectively support memory generation have remained elusive. Here we show that an immunization regimen that delivers TCR signals through a defined antigenic peptide, inflammatory signals through LPS, and growth and differentiation signals through the IL-2R initially favors antigen-specific CD8+ T cells to rapidly and substantially develop into tissue-residing T effector-memory cells by TCR transgenic OVA-specific OT-I CD8+ T cells. Amplified CD8+ T memory development depends upon a critical frequency of antigen-specific T cells and direct responsiveness to IL-2. A homologous prime-boost immunization protocol with transiently enhanced IL-2R signaling in normal mice led to persistent polyclonal antigen-specific CD8+ T cells that supported protective immunity to Listeria monocytogenes. These results identify a general approach for amplified T memory development that may be useful to optimize vaccines aimed at generating robust cell-mediated immunity. Gene expression analysis was performed for OT-I T cells on day 3 and day 5 after activation with ovalbumin and LPS in vivo with and without treatment with IL-2 using an agonists IL-2/anti-IL-2 complexes (IL2/Jes-6.1) OT-I T cells were purified and adoptively transferred into congenic syngenic mice. 24 hours later mice were immunization with ovalbumin and LPS. 24 hr later some mice received agonist IL2/anti-IL2. 3 and 5 days after immunization, the activated OT-I T cells were purifed by FACS and total RNA was isolated for genome wide expression analysis using Affymetrix Mouse Gene ST1.0 arrays

2012-10-03 | E-GEOD-39110 | biostudies-arrayexpress

Mus musculus

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

| PRJNA242918 | ENA

Identification of different human CD8 T cell subsets by superior cytotoxicity in human T cells

Project description:Cytotoxic CD8+ T cells can effectively kill target cells by producing cytokines, chemokines and granzymes. Expression of these effector molecules is however highly divergent, and tools that identify and pre-select potent killer cells are lacking. Human CD8+ T cells can be divided into IFNGand IL-2 producing cells. Unbiased RNA-sequencing and proteomics analysis on cytokine-producing fixed CD8+ T cells revealed that IL-2+ T cells produce helper cytokines, and that IFNG+ T cells produce cytotoxic molecules. IFNG+ cytotoxic T cells expressed the surface marker CD29 already prior to stimulation. CD29 also marked T cells with cytotoxic gene expression from different tissues in single-cell RNA-sequencing data. Notably, the cytotoxic features of CD29+ T cells were maintained during cell culture, suggesting a stable phenotype. Pre-selecting CD29-expressing MART1 TCR-engineered T cells potentiated the killing of target cells. We therefore propose that selecting for CD29+ T cells could boost the anti-tumoral activity of T cell therapeutics.

2021-09-08 | PXD012874 | Pride

Expression analysis of G9C8 clone and NOD.G9C8 tg CTLs

Project description:Diabetogenic CD8+ G9C8 clone cells and the T cells from a transgenic mouse bearing the same TCR as the clone, displayed differences in their ability to induce disease in vivo.Microarray analysis was done to identify the molecular basis for such differences between the two sets of CD8 T cells. Microarray analysis was done to identify the molecular basis for such differences between the two sets of CD8 T cells 3 vials of frozen G9C8 clone cells and spleen cells from 2 NOD.G9C8 transgenic mice were similarly peptide stimulated for 3 days and rested in IL2 for 2 days in order to obtain uniformly activated cells for analysis.

2012-12-04 | E-GEOD-31726 | biostudies-arrayexpress

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

APMAT analysis reveals associations between antigen-TCR sequences and CD8 T cell phenotype in COVID-19 patients

Project description:Here, we describe Antigen-TCR Pairing and Multiomic Analysis of T-cells (APMAT), which is an integrated experimental-computational framework designed for the high-throughput capture and analysis of antigen specific CD8 T cells, with paired antigen, TCR sequence, and transcriptome information from the same single cells, from many patient samples in parallel.

2024-09-18 | E-MTAB-14002 | biostudies-arrayexpress

Transcription profiling of primary CD8+ T cell activation

Project description:Little is known about the global transcriptional program underlying CD8+ T-cell activation. Using DNA microarrays and Q-RT-PCR, we examined the transcriptional profile of human CD8+ T-cell activation. The goal of this study was to identify genes involved in the various facets of human CD8+ T-cell activation. Experiment Overall Design: CD8+ T cells isolated from peripheral blood were cultured with CD3, CD28, with or without IL-2 to induce T-cell activation. At each timepoint, cells were harvested and frozen for RNA isolation. Three biological replicate experiments were analyzed and approximately one-half of the samples from each experiment were technically replicated. Hybridizations were performed in a reference design with all samples labeled with Cy3 and a reference thymus total RNA labeled with Cy5.

2008-06-15 | E-GEOD-7572 | biostudies-arrayexpress

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

Single-cell multiomic analysis of thymocyte development reveals drivers of CD4+ T cell and CD8+ T cell lineage commitment

Project description:The development of CD4+ T cells and CD8+ T cells in the thymus is critical to adaptive immunity and is widely studied as a model of lineage commitment. Recognition of self-MHCI or MHCII by the T cell antigen receptor (TCR) determines the CD8+ T cell or CD4+ T cell lineage choice, respectively, but how distinct TCR signals drive transcriptional programs of lineage commitment remains largely unknown. Here we applied CITE-seq to measure RNA and surface proteins in thymocytes from wild-type and T cell lineage-restricted mice to generate a comprehensive timeline of cell state for each T cell lineage. These analyses identified a sequential process whereby all thymocytes initiate CD4+ T cell lineage differentiation during an initial wave of TCR signaling, followed by a second TCR signaling wave that coincides with CD8+ T cell lineage specification. CITE-seq and pharmaceutical inhibition experiments implicated a TCR-calcineurin-NFAT-GATA3 axis in driving the CD4+ T cell fate. Our data provide a resource for understanding cell fate decisions and implicate multiple redundant mechanisms in guiding lineage choice.

2023-06-30 | GSE186078 | GEO

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