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.

Keywords: Diabetology; Immunology; Proteomics.