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- Title
Recognition of mRNA Splice Variant and Secretory Granule Epitopes by CD4<sup>+</sup> T Cells in Type 1 Diabetes.
- Authors
Guyer, Perrin; Arribas-Layton, David; Manganaro, Anthony; Speake, Cate; Lord, Sandra; Eizirik, Decio L.; Kent, Sally C.; Mallone, Roberto; James, Eddie A.
- Abstract
A recent discovery effort resulted in identification of novel splice variant and secretory granule antigens within the HLA class I peptidome of human islets and documentation of their recognition by CD8+ T cells from peripheral blood and human islets. In the current 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 those of 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.
- Subjects
SECRETORY granules; T cells; TYPE 1 diabetes; EPITOPES; RECOGNITION (Psychology); HLA histocompatibility antigens
- Publication
Diabetes, 2023, Vol 72, Issue 1, p85
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db22-0191