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Obesity Reshapes Visceral Fat-Derived MHC I Associated-Immunopeptidomes and Generates Antigenic Peptides to Drive CD8⁺ T Cell Responses.

ABSTRACT: Adaptive CD8⁺ T cells were observed to contribute to the initiation and progression of obesity-induced visceral adipose tissue (VAT) chronic inflammation that is critically linked to metabolic disorders. Numerous peptides presented by the major histocompatibility complex (MHC) class I molecules at the cell surface are collectively termed as MHC I-associated immunopeptidome (MIP) for the interaction with CD8⁺ T cells. We conducted the in-depth mapping of MIP of VAT from lean and obese mice using large-scale high-resolution mass spectrometry and observed that obesity significantly alters the landscape of VAT MIPs. Additionally, the obese VAT-exclusive MIP source proteome reflected a distinct obesity-associated signature. A peptide derived from lactate dehydrogenase A (LDHA) or B chain, named LDHA_237-244, was identified as an obese VAT-exclusive immunogenic peptide that was capable of eliciting pro-inflammatory CD8⁺ T cells responses. Our findings suggest that certain immunogenic peptides generated by obesity may trigger CD8⁺ T cell-mediated VAT inflammation.

SUBMITTER: Chen X

PROVIDER: S-EPMC7109454 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Obesity Reshapes Visceral Fat-Derived MHC I Associated-Immunopeptidomes and Generates Antigenic Peptides to Drive CD8+ T Cell Responses.

Chen Xiaoling X Wang Shufeng S Huang Yi Y Zhao Xia X Jia Xu X Meng Gang G Zheng Qian Q Zhang Mengjun M Wu Yuzhang Y Wang Li L

iScience 20200313 4

Adaptive CD8+ T cells were observed to contribute to the initiation and progression of obesity-induced visceral adipose tissue (VAT) chronic inflammation that is critically linked to metabolic disorders. Numerous peptides presented by the major histocompatibility complex (MHC) class I molecules at the cell surface are collectively termed as MHC I-associated immunopeptidome (MIP) for the interaction with CD8+ T cells. We conducted the in-depth mapping of MIP of VAT from lean ...[more]

PMID: 32217358

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Project description:Background & aims24-Norursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid used to treat immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC), where dysregulated T cells including CD8+ T cells contribute to hepatobiliary immunopathology. We hypothesized that NorUDCA may directly modulate CD8+ T cell function thus contributing to its therapeutic efficacy.MethodsNorUDCA's immunomodulatory effects were first studied in Mdr2-/- mice, as a cholestatic model of PSC. To differentiate NorUDCA's immunomodulatory effects on CD8+ T cell function from its anticholestatic actions, we also used a non-cholestatic model of hepatic injury induced by an excessive CD8+ T cell immune response upon acute non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Studies included molecular and biochemical approaches, flow cytometry and metabolic assays in murine CD8+ T cells in vitro. Mass spectrometry was used to identify potential CD8+ T cell targets modulated by NorUDCA. The signaling effects of NorUDCA observed in murine cells were validated in circulating T cells from patients with PSC.ResultsNorUDCA demonstrated immunomodulatory effects by reducing hepatic innate and adaptive immune cells, including CD8+ T cells in the Mdr2-/- model. In the non-cholestatic model of CD8+ T cell-driven immunopathology induced by acute LCMV infection, NorUDCA ameliorated hepatic injury and systemic inflammation. Mechanistically, NorUDCA demonstrated strong immunomodulatory efficacy in CD8+ T cells affecting lymphoblastogenesis, expansion, glycolysis and mTORC1 signaling. Mass spectrometry identified that NorUDCA regulates CD8+ T cells by targeting mTORC1. NorUDCA's impact on mTORC1 signaling was further confirmed in circulating PSC CD8+ T cells.ConclusionsNorUDCA has a direct modulatory impact on CD8+ T cells and attenuates excessive CD8+ T cell-driven hepatic immunopathology. These findings are relevant for treatment of immune-mediated liver diseases such as PSC.Lay summaryElucidating the mechanisms by which 24-norursodeoxycholic acid (NorUDCA) works for the treatment of immune-mediated liver diseases, such as primary sclerosing cholangitis, is of considerable clinical interest. Herein, we uncovered an unrecognized property of NorUDCA in the immunometabolic regulation of CD8+ T cells, which has therapeutic relevance for immune-mediated liver diseases, including PSC.

Dataset Information

Obesity Reshapes Visceral Fat-Derived MHC I Associated-Immunopeptidomes and Generates Antigenic Peptides to Drive CD8⁺ T Cell Responses.

Publications

Obesity Reshapes Visceral Fat-Derived MHC I Associated-Immunopeptidomes and Generates Antigenic Peptides to Drive CD8<sup>+</sup> T Cell Responses.

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