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

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-peptide...

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Autores principales: Nguyen, Hai, Arribas-Layton, David, Chow, I-Ting, Speake, Cate, Kwok, William W., Hessner, Martin J., Greenbaum, Carla J., James, Eddie A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9871889/
https://www.ncbi.nlm.nih.gov/pubmed/36703975
http://dx.doi.org/10.3389/fimmu.2022.1015855
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author Nguyen, Hai
Arribas-Layton, David
Chow, I-Ting
Speake, Cate
Kwok, William W.
Hessner, Martin J.
Greenbaum, Carla J.
James, Eddie A.
author_facet Nguyen, Hai
Arribas-Layton, David
Chow, I-Ting
Speake, Cate
Kwok, William W.
Hessner, Martin J.
Greenbaum, Carla J.
James, Eddie A.
author_sort Nguyen, Hai
collection PubMed
description 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.
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spelling pubmed-98718892023-01-25 Characterizing T cell responses to enzymatically modified beta cell neo-epitopes Nguyen, Hai Arribas-Layton, David Chow, I-Ting Speake, Cate Kwok, William W. Hessner, Martin J. Greenbaum, Carla J. James, Eddie A. Front Immunol Immunology 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. Frontiers Media S.A. 2023-01-10 /pmc/articles/PMC9871889/ /pubmed/36703975 http://dx.doi.org/10.3389/fimmu.2022.1015855 Text en Copyright © 2023 Nguyen, Arribas-Layton, Chow, Speake, Kwok, Hessner, Greenbaum and James https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Nguyen, Hai
Arribas-Layton, David
Chow, I-Ting
Speake, Cate
Kwok, William W.
Hessner, Martin J.
Greenbaum, Carla J.
James, Eddie A.
Characterizing T cell responses to enzymatically modified beta cell neo-epitopes
title Characterizing T cell responses to enzymatically modified beta cell neo-epitopes
title_full Characterizing T cell responses to enzymatically modified beta cell neo-epitopes
title_fullStr Characterizing T cell responses to enzymatically modified beta cell neo-epitopes
title_full_unstemmed Characterizing T cell responses to enzymatically modified beta cell neo-epitopes
title_short Characterizing T cell responses to enzymatically modified beta cell neo-epitopes
title_sort characterizing t cell responses to enzymatically modified beta cell neo-epitopes
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9871889/
https://www.ncbi.nlm.nih.gov/pubmed/36703975
http://dx.doi.org/10.3389/fimmu.2022.1015855
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