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Article Dans Une Revue Diabetes Année : 2022

Recognition of mRNA Splice Variant and Secretory Granule Epitopes by CD4+ T Cells in Type 1 Diabetes

Résumé

A recent discovery effort identified novel splice variant and secretory granule antigens within the HLA class I peptidome of human islets and documented their recognition by CD8 + T cells from peripheral blood and human islets. In the present study, we applied a systematic discovery process to identify novel CD4+ T cell epitopes derived from these candidate antigens. We predicted 145 potential epitopes spanning unique splice junctions and within conventional secretory granule antigens and measured their in vitro binding to DRB1*04:01. We generated HLA class II tetramers for the 35 peptides with detectable binding and used these to assess immunogenicity and isolate T cell clones. Tetramers corresponding to peptides with verified immunogenicity were then used to label T cells specific for these putative epitopes in peripheral blood. T cells that recognize distinct epitopes derived from a cyclin I splice variant, neuroendocrine convertase 2, and urocortin-3 were detected at frequencies that were similar to an immunodominant proinsulin epitope. Cells specific for these novel epitopes predominantly exhibited a Th1-like surface phenotype. Among the three epitopes, responses to the cyclin I peptide exhibited a distinct memory profile. Responses to neuroendocrine convertase 2 were detected among pancreatic infiltrating T cells. These results further establish the contribution of unconventional antigens to the loss of tolerance in autoimmune diabetes.
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Dates et versions

inserm-03837621 , version 1 (03-11-2022)

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Citer

Perrin Guyer, David Arribas-Layton, Anthony Manganaro, Cate Speake, Sandra Lord, et al.. Recognition of mRNA Splice Variant and Secretory Granule Epitopes by CD4+ T Cells in Type 1 Diabetes. Diabetes, 2022, Online ahead of print. ⟨10.2337/db22-0191⟩. ⟨inserm-03837621⟩
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