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MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T cell responses

ABSTRACT: MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T cell responses

PROVIDER: PRJEB57978 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR10557469_1.fastq.gz	Fastqsanger.gz
	ERR10557469_2.fastq.gz	Fastqsanger.gz
	ERR10557470_1.fastq.gz	Fastqsanger.gz
	ERR10557470_2.fastq.gz	Fastqsanger.gz
	ERR10557471_1.fastq.gz	Fastqsanger.gz

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MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T cell responses

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Project description:Single cell ATAC sequencing of SIINFEKL-reactive immune cell from intracranial murine GL261-SIINFEKL tumors 20 days after inoculation. SIINFEKL-reactive T cells were sorted based on dextramer staining. We show that loss of major histocompatibility complex (MHC) class II (MHCII)-restricted antigen presentation on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion.

2023-01-11 | E-MTAB-12512 | biostudies-arrayexpress

Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I (SureQuant data)

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An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer [RNA-Seq]

Project description:Loss of MHC class I (MHC-I) antigen presentation in cancer cells can lead to immunotherapy resistance. Using a genome-wide CRISPR/Cas9 screen we identify a critical role for polycomb repressive complex 2 (PRC2) in the coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP). This evolutionarily conserved function of PRC2 promotes evasion of T-cell mediated immunity, enabling tumour transmission to non-histocompatible recipients in small cell lung cancer (SCLC) and Tasmanian Devil Facial Tumour. MHC-I APP gene promoters in MHC-I low cancers harbour bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine induced MHC-I APP gene upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological silencing of MHC-I expression highlights a conserved mechanism by which cancers arising from these primitive tissues coopt PRC2 activity to enable immune evasion.

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An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer [ChIP-Seq]

Project description:Loss of MHC class I (MHC-I) antigen presentation in cancer cells can lead to immunotherapy resistance. Using a genome-wide CRISPR/Cas9 screen we identify a critical role for polycomb repressive complex 2 (PRC2) in the coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP). This evolutionarily conserved function of PRC2 promotes evasion of T-cell mediated immunity, enabling tumor transmission to non-histocompatible recipients in small cell lung cancer (SCLC) and Tasmanian Devil Facial Tumor. MHC-I APP gene promoters in MHC-I low cancers harbour bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine induced MHC-I APP gene upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological silencing of MHC-I expression highlights a conserved mechanism by which cancers arising from these primitive tissues coopt PRC2 activity to enable immune evasion.

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2020-01-29 | PXD014644 | Pride

Longitudinal scRNA-Seq of immune cells from GL261 murine brain Tumors and MHC class II deficient tumor-mircoenvironments

Project description:Longitudinal phenotyping of T cells and myeloid cells in early (day 14) and late (day26) GL261 tumors. Single cell RNA sequencing of CD45+ immune cell from intracranial murine GL261-SIINFEKL tumors 20 days after inoculation. SIINFEKL-reactive T cells were sorted based on dextramer staining. Using time-resolved scRNA-seq of murine tumor-infiltrating immune cells from early (d14) and late stage (d26) syngeneic GL261 gliomas we observed constant MHCII expression by murine microglia over time and overall high but decreasing MHCII expression in late stage bbm indicating a dynamic process of MHCII expression. We show that loss of major histocompatibility complex (MHC) class II (MHCII)-restricted antigen presentation on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased expression of Tox, a critical regulator of T cell exhaustion. By calculating the normalized abundance of T cell states along the pseudotime trajectory of SIINFEKL-reactive CD8+ T cells retrieved from myeloidMHCII-proficient and -deficient microenvironments, we found an enrichment of a distinct T cell state in myeloidMHCIIKO CD8+ T cells that was defined by peak expression of exhaustion markers. Mechanistically, MHCII-dependent activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of nuclear factor of activated T cells (Nfat)2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors.

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Project description:MHC class I (MHC-I)-mediated tumor antigen processing and presentation (APP) pathway is essential for recruitment and activation of cytotoxic CD8+ T lymphocytes (CD8+ CTLs). However, this pathway is frequently dysregulated in many cancers, thus leading to a failure of immunotherapy. Here, we reported that activation of the tumoral intrinsic Hippo pathway positively correlated with the expression of MHC-I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector YAP/TEAD potently improved antitumor immunity. Mechanistically, the YAP/TEAD complex cooperated with the NuRD complex to repress the NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increased the expression of MHC-I APP genes and enhanced CD8+ CTLmediated killing of cancer cells. Collectively, our results suggest a novel tumorpromoting function of YAP depending on NLRC5 to impair MHC-I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer.

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Project description:Activated SUMOylation is a hallmark of aggressive cancers. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionary conserved function of activated SUMOylation, which attenuates the immunogenicity of tumor cells. Activated SUMOylation allows cancer cells to evade CD8+ T-cell immunosurveillance by repressing the MHC-I antigen processing and presentation machinery (APM). While loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, the pharmacological inhibition of SUMOylation (SUMOi) restored the expression of the MHC-I APM and enhanced the susceptibility of tumor cells to CD8+ T-cell mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T-cells itself and thereby drives a feed-forward loop amplifying the specific anti-tumor immune response. In summary, we show that activated SUMOylation converts tumor cells into a state of immune evasion, and identify SUMOi as rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.

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