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NFAT5 induction by the tumor microenvironment enforces CD8 T cell exhaustion (CUT&Tag)

ABSTRACT: Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. We discovered that NFAT5, an NFAT family member lacking an AP-1 docking site, is highly expressed in exhausted T cells responding to chronic infection and tumors but is a central player selectively in tumor-induced exhaustion. While NFAT5 overexpression in CD8+ T cells reduced tumor control, NFAT5 deletion improved tumor control by promoting the accumulation of tumor-specific CD8 T cells that expressed less TOX and PD-1 and produced more cytokines specifically among precursor exhausted cells. Conversely, NFAT5 did not promote T cell exhaustion during chronic infection. While NFAT5 expression was induced by TCR triggering, its transcriptional activity was specific to the tumor microenvironment and required hyperosmolarity. NFAT5 thus promotes CD8 T cell exhaustion in a tumor-selective fashion.

ORGANISM(S): Mus musculus

PROVIDER: GSE237313 | GEO | 2023/07/18

REPOSITORIES: GEO

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NFAT5 induction by the tumor microenvironment enforces CD8 T cell exhaustion [ATAC]

Project description:Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. We discovered that NFAT5, an NFAT family member lacking an AP-1 docking site, is highly expressed in exhausted T cells responding to chronic infection and tumors but is a central player selectively in tumor-induced exhaustion. While NFAT5 overexpression in CD8+ T cells reduced tumor control, NFAT5 deletion improved tumor control by promoting the accumulation of tumor-specific CD8 T cells that expressed less TOX and PD-1 and produced more cytokines specifically among precursor exhausted cells. Conversely, NFAT5 did not promote T cell exhaustion during chronic infection. While NFAT5 expression was induced by TCR triggering, its transcriptional activity was specific to the tumor microenvironment and required hyperosmolarity. NFAT5 thus promotes CD8 T cell exhaustion in a tumor-selective fashion.

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NFAT5 induction by the tumor microenvironment enforces CD8 T cell exhaustion

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CD39 expression identifies terminally exhausted CD8+ T cells

Project description:Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. CD8+ T cells from subjects with HCV infection were sorted and pelleted and re-suspended in TRIzol (Invitrogen). RNA extraction was performed using the RNAdvance Tissue Isolation kit (Agencourt). Concentrations of total RNA were determined with a Nanodrop spectrophotometer or Ribogreen RNA quantification kits (Molecular Probes/Invitrogen). RNA purity was determined by Bioanalyzer 2100 traces (Agilent Technologies). Total RNA was amplified with the WT-Ovation Pico RNA Amplification system (NuGEN) according to the manufacturer's instructions. After fragmentation and biotinylation, cDNA was hybridized to HG-U133A 2.0 microarrays (Affymetrix).

2015-09-08 | E-GEOD-72752 | biostudies-arrayexpress

CD39 expression identifies terminally exhausted CD8+ T cells

2015-09-08 | GSE72752 | GEO

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Project description:Chronic viral infections are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with naÃ¯ve CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy. 8 samples isolated from CD8 T-cells in LCMV clone 13 GK1.5 infected mice (2 naÃ¯ve, 3 CXCR5+Tim3-, 3 CXCR5-Tim3+) cells were analyzed

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| EGAS00001004538 | EGA

dd195318-5103-4c2e-9845-d48e04787b77 - samples

| EGAD00001006259 | EGA

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