AUTHOR=Nguyen Hai , Arribas-Layton David , Chow I-Ting , Speake Cate , Kwok William W. , Hessner Martin J. , Greenbaum Carla J. , James Eddie A. 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1015855

DOI=10.3389/fimmu.2022.1015855

ISSN=1664-3224

ABSTRACT=Previous studies verify the formation of enzymatically modified 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 modified self-peptides derived from different antigens, their functional phenotypes, and whether their presence correlates with a specific disease endotype. To address this question, we recruited a cohort of subjects with T1D who had high or low levels of residual beta cell function. Using previously developed HLA class II tetramer reagents, we directly enumerated T cells that recognize modified GAD65 epitopes in the context of DRB1*04:01 or modified IA-2 epitopes in the context of DQB1*03:02 (DQ8).  Consistent with prior studies, we observed higher overall frequencies in subjects with T1D than in HLA matched controls.  Notably, DQ8 restricted responses to modified IA-2 were over-represented in subjects with lower residual beta cell function. T cells specific for both groups of epitopes could be expanded from the peripheral blood of subjects with established T1D and at risk subjects.  These neo-epitope specific T cells had similar functional profiles in subjects with T1D and primarily produced interferon gamma.  Neo-epitope specific T cells in at risk subjects with multiple antibodies produced higher amounts of interferon gamma and lower amounts of IL-4 than at risk subjects with single antibodies, suggesting a shift in polarization during progression. These results reinforce the relevance of modified neo-epitopes in human disease and indicate that responses to distinct neo-antigens accompany a more rapid decline in beta cell function.