Characterizing T cell responses to enzymatically modified beta cell neo-epitopes

Front Immunol. 2023 Jan 10:13:1015855. doi: 10.3389/fimmu.2022.1015855. eCollection 2022.

Abstract

Introduction: Previous studies verify the formation of enzymatically post-translationally modified (PTM) self-peptides and their preferred recognition by T cells in subjects with type 1 diabetes (T1D). However, questions remain about the relative prevalence of T cells that recognize PTM self-peptides derived from different antigens, their functional phenotypes, and whether their presence correlates with a specific disease endotype.

Methods: To address this question, we identified a cohort of subjects with T1D who had diverse levels of residual beta cell function. Using previously developed HLA class II tetramer reagents, we enumerated T cells that recognize PTM GAD epitopes in the context of DRB1*04:01 or PTM IA2 epitopes in the context of DQB1*03:02 (DQ8).

Results: Consistent with prior studies, we observed higher overall frequencies and a greater proportion of memory T cells in subjects with T1D than in HLA matched controls. There were significantly higher numbers of GAD specific T cells than IA2 specific T cells in subjects with T1D. T cells specific for both groups of epitopes could be expanded from the peripheral blood of subjects with established T1D and at-risk subjects. Expanded neo-epitope specific T cells primarily produced interferon gamma in both groups, but a greater proportion of T cells were interferon gamma positive in subjects with T1D, including some poly-functional cells that also produced IL-4. Based on direct surface phenotyping, neo-epitope specific T cells exhibited diverse combinations of chemokine receptors. However, the largest proportion had markers associated with a Th1-like phenotype. Notably, DQ8 restricted responses to PTM IA2 were over-represented in subjects with lower residual beta cell function. Neo-epitope specific T cells were present in at-risk subjects, and those with multiple autoantibodies have higher interferon gamma to IL-4 ratios than those with single autoantibodies, suggesting a shift in polarization during progression.

Discussion: These results reinforce the relevance of PTM neo-epitopes in human disease and suggest that distinct responses to neo-antigens promote a more rapid decline in beta cell function.

Keywords: T cell; Type 1 diabetes (T1D); at risk; citrullinated autoantigens; deamidated autoantigens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies
  • Diabetes Mellitus, Type 1*
  • Epitopes
  • Humans
  • Interferon-gamma
  • Interleukin-4
  • Peptides
  • T-Lymphocytes* / immunology

Substances

  • Autoantibodies
  • Epitopes
  • Interferon-gamma
  • Interleukin-4
  • Peptides

Grants and funding

This work was supported by JDRF grant 2-SRA-2018-551-S-B (EJ). Sample and clinical data collection by the T1D exchange was supported by the Helmsley Charitable Trust.