Characterization of proinsulin T cell epitopes restricted by type 1 diabetes-associated HLA Class II molecules

Emmi Leena Ihantola, Henna Ilmonen, Anssi Kailaanmäki, Marja Rytkönen-Nissinen, Aurélien Azam, Bernard Maillère, Cecilia S.Lindestam Arlehamn, Alessandro Sette, Keshav Motwani, Howard R. Seay, Todd M. Brusko, Mikael Knip, Riitta Veijola, Jorma Toppari, Jorma Ilonen, Tuure Kinnunen

    Research output: Contribution to journalArticleScientificpeer-review

    13 Citations (Scopus)

    Abstract

    Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease in which the insulin-producing b cells within the pancreas are destroyed. Identification of target Ags and epitopes of the β cell-reactive T cells is important both for understanding T1D pathogenesis and for the rational development of Ag-specific immunotherapies for the disease. Several studies suggest that proinsulin is an early and integral target autoantigen in T1D. However, proinsulin epitopes recognized by human CD4+ T cells have not been comprehensively characterized. Using a dye dilution-based T cell cloning method, we generated and characterized 24 unique proinsulin-specific CD4+ T cell clones from the peripheral blood of 17 individuals who carry the high-risk DR3-DQ2 and/or DR4-DQ8 HLA class II haplotypes. Some of the clones recognized previously reported DR4-restricted epitopes within the C-peptide (C25-35) or A-chain (A1-15) of proinsulin. However, we also characterized DR3-restricted epitopes within both the Bchain (B16-27 and B22-C3) and C-peptide (C25-35). Moreover, we identified DQ2-restricted epitopes within the B-chain and several DQ2- or DQ8-restricted epitopes within the C-terminal region of C-peptide that partially overlap with previously reported DQ-restricted epitopes. Two of the DQ2-restricted epitopes, B18-26 and C22-33, were shown to be naturally processed from whole human proinsulin. Finally, we observed a higher frequency of CDR3 sequences matching the TCR sequences of the proinsulinspecific T cell clones in pancreatic lymph node samples compared with spleen samples. In conclusion, we confirmed several previously reported epitopes but also identified novel (to our knowledge) epitopes within proinsulin, which are presented by HLA class II molecules associated with T1D risk.

    Original languageEnglish
    Pages (from-to)2349-2359
    Number of pages11
    JournalJournal of immunology
    Volume204
    Issue number9
    DOIs
    Publication statusPublished - 2020
    Publication typeA1 Journal article-refereed

    Funding

    This work was supported by the Academy of Finland (Decision 307320), the Sigrid Jusélius Foundation, State Research Funding (VTR), and the Finnish Diabetes Research Foundation. The Finnish Type 1 Diabetes Prediction and Prevention study was supported by the Academy of Finland (Decisions 250114 and 286765), the Sigrid Jusélius Foundation, and the Juvenile Diabetes Research Foundation International (JDRF). The Network for Pancreatic Organ Donors with Diabetes is supported by the JDRF, with cooperative mechanistic study support by The Leona M. and Harry B. Helmsley Charitable Trust (to T.M.B.). The funders had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; and in the preparation, review, or approval of the manuscript.

    Publication forum classification

    • Publication forum level 2

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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