Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 14; pp. 4429 - 4434
• Main Authors: Nakayama, Maki, McDaniel, Kristen, Fitzgerald-Miller, Lisa, Carol, Kiekhaefer, Snell-Bergeona, Janet K., Davidson, Howard W., Rewers, Marian, Yu, Liping, Gottlieb, Peter, Kappler, John W., Michels, Aaron
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.04.2015; National Acad Sciences
• Subjects: Adolescent; Adult; alleles; Amino Acid Sequence; Animals; autoantibodies; Autoantibodies - metabolism; Biological Sciences; CD4-positive T-lymphocytes; CD4-Positive T-Lymphocytes - metabolism; Child; Cytokines; Cytokines - metabolism; Diabetes; Diabetes Mellitus, Type 1 - metabolism; disease prevention; Female; Genotype; HLA-DQ Antigens - genetics; Humans; Inflammation - metabolism; Insulin; Insulin - genetics; Insulin - metabolism; insulin-dependent diabetes mellitus; Interferon-gamma - metabolism; Interleukin-10 - metabolism; Male; Mice; Mice, Inbred NOD; Middle Aged; Molecular Sequence Data; monitoring; Mutation; Peptides; Receptors, Antigen, T-Cell - metabolism; risk; Risk assessment; Sequence Homology, Amino Acid; T cell receptors; Young Adult; CD4 T cells; autoimmunity; insulin; self-tolerance; diabetes
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1502967112

Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9–23) mimotopes engineered to bind the mouse MHCII molecule, IA ᵍ⁷, in an unfavorable position or register. Because of the similarities between IA ᵍ⁷ and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9–23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9–23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulin-specific therapies to prevent diabetes onset. Significance Certain class II major histocompatibility alleles confer disease risk for type 1 diabetes (T1D). Insulin-specific and other autoantibodies often precede T1D development, but major efforts at disease prevention using insulin preparations (subcutaneous, oral, and intranasal) to induce tolerance have not been effective. Measuring insulin-specific T-cell responses from the peripheral blood has been a challenging feat but would allow for assessment of therapeutic response in these trials. In our study, we report CD4 T-cell responses to a mutated insulin B-chain peptide in new-onset and established T1D as well as control subjects dependent on HLA-DQ genotype. Our results have important implications for the application and monitoring of insulin-specific therapies to prevent diabetes onset.