Characterization of Proinsulin T Cell Epitopes Restricted by Type 1 Diabetes–Associated HLA Class II Molecules
Year: 2020
Type: article
Abstract: Type 1 diabetes (T1D) is a T cell–mediated autoimmune disease in which the insulin-producing β 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 B-chain (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 proinsulin-specific 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.
Source: The Journal of Immunology
Institutions: University of Eastern Finland, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, CEA Paris-Saclay, La Jolla Institute for Immunology, University of California San Diego, University of Florida Health, University of Florida, University of Helsinki, Helsinki University Hospital, Helsinki Children's Hospital, Tampere University Hospital, Folkhälsans Forskningscentrum, Oulu University Hospital, University of Oulu, University of Turku, Turku University Hospital, Eastern Finland Laboratory Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Juvenile Diabetes Research Foundation International, Leona M. and Harry B. Helmsley Charitable Trust, Itä-Suomen Yliopisto, Academy of Finland, Turun Yliopisto, Sigrid Juséliuksen Säätiö, Diabetesliitto, Novo Nordisk Fonden, Diabetestutkimussäätiö, National Institute of Allergy and Infectious Diseases
OpenAlex ID: W3013291452