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Characterization of Proinsulin T Cell Epitopes Restricted by Type 1 Diabetes-Associated HLA Class II Molecules

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

The Journal of immunology (1950), 2020-05, Vol.204 (9), p.2349-2359 [Periódico revisado por pares]

United States: Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists

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Título:
Characterization of Proinsulin T Cell Epitopes Restricted by Type 1 Diabetes-Associated HLA Class II Molecules
Autor: Ihantola, Emmi-Leena ; Ilmonen, Henna ; Kailaanmäki, Anssi ; Rytkönen-Nissinen, Marja ; Azam, Aurélien ; Maillère, Bernard ; Lindestam Arlehamn, Cecilia S ; Sette, Alessandro ; Motwani, Keshav ; Seay, Howard R ; Brusko, Todd M ; Knip, Mikael ; Veijola, Riitta ; Toppari, Jorma ; Ilonen, Jorma ; Kinnunen, Tuure
Assuntos: Adolescent ; Amino Acid Sequence ; Autoantigens ; Autoantigens - immunology ; CD4-Positive T-Lymphocytes ; CD4-Positive T-Lymphocytes - immunology ; Child ; Child, Preschool ; Diabetes Mellitus, Type 1 ; Diabetes Mellitus, Type 1 - immunology ; Epitopes, T-Lymphocyte ; Epitopes, T-Lymphocyte - immunology ; HLA-DQ Antigens ; HLA-DQ Antigens - immunology ; HLA-DQ8 antigen ; Human health sciences ; Humans ; Immunologie & maladie infectieuse ; Immunology ; Immunology & infectious disease ; Immunology and Allergy ; Infant ; Insulin ; Insulin - immunology ; Insulin-Secreting Cells ; Insulin-Secreting Cells - immunology ; Life Sciences ; Proinsulin ; Proinsulin - immunology ; Sciences de la santé humaine ; Spleen ; Spleen - immunology
É parte de: The Journal of immunology (1950), 2020-05, Vol.204 (9), p.2349-2359
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
scopus-id:2-s2.0-85084048017
Descrição: 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.
Editor: United States: Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists
Idioma: Inglês

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Characterization of Proinsulin T Cell Epitopes Restricted by Type 1 Diabetes-Associated HLA Class II Molecules

United States: Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists

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