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

• Published in: Frontiers in immunology 2023-01, Vol.13, p.1015855-1015855
• Main Authors: Nguyen, Hai, Arribas-Layton, David, Chow, I-Ting, Speake, Cate, Kwok, William W, Hessner, Martin J, Greenbaum, Carla J, James, Eddie A
• Format: Article
• Language: English
• Subjects: at risk; Autoantibodies; citrullinated autoantigens; deamidated autoantigens; Diabetes Mellitus, Type 1; Epitopes; Humans; Immunology; Interferon-gamma; Interleukin-4; Peptides; T cell; T-Lymphocytes - immunology; Type 1 diabetes (T1D)
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.1015855

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. 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). 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. 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.