Proinsulin C-peptide is a major source of HLA-DQ8 restricted hybrid insulin peptides recognized by human islet-infiltrating CD4(+) T cells

Bhattacharjee, P; Pakusch, M; Lacorcia, M; Tresoldi, E; Rubin, AF; Foster, A; King, L; Chiu, CY; Kay, TWH; Karas, JA; Cameron, FJ; Mannering, SI

Author(s): Bhattacharjee, P; Pakusch, M; Lacorcia, M; Tresoldi, E; Rubin, AF; Foster, A; King, L; Chiu, CY; Kay, TWH; Karas, JA; Cameron, FJ; Mannering, SI;
Details: Publication Year 2024-11,Volume 3,Issue #11,Page pgae491
Journal Title: PNAS Nexus
Abstract: Type 1 diabetes (T1D) is an autoimmune disease that develops when T cells destroy the insulin-producing beta cells that reside in the pancreatic islets. Immune cells, including T cells, infiltrate the islets and gradually destroy the beta cells. Human islet-infiltrating CD4(+) T cells recognize peptide epitopes derived from proinsulin, particularly C-peptide. Hybrid insulin peptides (HIPs) are neoepitopes formed by the fusion of two peptides derived from beta cell granule proteins and are known to be the targets of pathogenic CD4(+) T cells in the non-obese diabetic (NOD) mouse and human islet-infiltrating CD4(+) T cells. Proinsulin is widely recognized as a central antigen in T1D, but its role in forming HIPs is unclear. We developed a method to functionally screen TCRs derived from human islet-infiltrating CD4(+) T cells and applied this to the identification of new proinsulin-derived HIPs. We generated a library of 4,488 candidate HIPs formed by fusion of proinsulin fragments and predicted to bind to HLA-DQ8. This library was screened against 109 islet-infiltrating CD4(+) T cell receptors (TCRs) isolated from four organ donors who had T1D. We identified 13 unique HIPs recognized by nine different TCRs from two organ donors. HIP-specific T cell avatars responded specifically to a peptide extract from human islets. These new HIPs predominantly stimulated CD4(+) T cell proliferation in peripheral blood mononuclear cells from individuals with T1D in contrast to HLA-matched controls. This is the first unbiased functional, islet-infiltrating T cell based, screen to identify proinsulin-derived HIPs. It has revealed many new HIPs and a central role of proinsulin C-peptide in their formation.
Publisher: Oxford Academic
Keywords: hybrid insulin peptides; islet-infiltrating CD4+ T cells; neoepitopes; type 1 diabetes
Research Division(s): Bioinformatics
PubMed ID: 39554513
Publisher's Version: https://doi.org/10.1093/pnasnexus/pgae491
Open Access at Publisher's Site: https://doi.org/10.1093/pnasnexus/pgae491
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-12-05 11:23:58

Last Modified: 2024-12-05 11:27:32