Pleiotropic consequences of metabolic stress for the major histocompatibility complex class II molecule antigen processing and presentation machinery

Cristina C. Clement, Padma P. Nanaware, Takahiro Yamazaki, Maria Pia Negroni, Karthik Ramesh, Kateryna Morozova, Sangeetha Thangaswamy, Austin Graves, Hei Jung Kim, Tsai Wanxia Li, Marco Vigano, Rajesh K. Soni, Massimo Gadina, Harley Y. Tse, Lorenzo Galluzzi, Paul A. Roche, Lisa K. Denzin, Lawrence J. Stern, Laura Santambrogio

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Hyperglycemia and hyperlipidemia are often observed in individuals with type II diabetes (T2D) and related mouse models. One dysmetabolic biochemical consequence is the non-enzymatic reaction between sugars, lipids, and proteins, favoring protein glycation, glycoxidation, and lipoxidation. Here, we identified oxidative alterations in key components of the major histocompatibility complex (MHC) class II molecule antigen processing and presentation machinery in vivo under conditions of hyperglycemia-induced metabolic stress. These modifications were linked to epitope-specific changes in endosomal processing efficiency, MHC class II-peptide binding, and DM editing activity. Moreover, we observed some quantitative and qualitative changes in the MHC class II immunopeptidome of Ob/Ob mice on a high-fat diet compared with controls, including changes in the presentation of an apolipoprotein B100 peptide associated previously with T2D and metabolic syndrome-related clinical complications. These findings highlight a link between glycation reactions and altered MHC class II antigen presentation that may contribute to T2D complications.

Original languageEnglish (US)
Pages (from-to)721-736.e10
JournalImmunity
Volume54
Issue number4
DOIs
StatePublished - Apr 13 2021

Keywords

  • CD4 T cells
  • MHC class II
  • advanced glycation end products
  • antigen processing and presentation
  • dendritic cells
  • diabetes
  • hyperinsulinemia
  • obesity
  • oxidative posttranslational modifications

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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