The Importance of CTLA-4 and HLA Class II for Type 1 Diabetes Immunology

Type 1 Diabetes (T1D) is a serious chronic disease that results from an autoimmune destruction of the insulin-producing beta cells. Sweden has the second highest incidence of T1D in the world, and it affects more and more children each year. Genes controlling key functions of the immune system regulation of autoimmunity has been associated to T1D. Polymorphism in the Human Leukocyte Antigen (HLA) Class II is a major risk determinant for T1D but also Cytotoxic T lymphocyte Antigen 4 (CTLA-4) polymorphism can affect predisposition. Immune responses towards Glutamic Acid Decarboxylase 65 (GAD65), Insulin, insulinoma-associated antigen 2 (IA-2) and Heat Shock protein 60 have all been implicated in T1D pathogenesis. We aimed to study the effect and role of CTLA-4 and HLA Class II in the T1D immunity. By focusing on the immune responses associated to T1D in healthy children with risk genotypes we aimed to study immunological effects of T1D risk. We found that HSP60-peptide induced a higher IFN-γ response in subjects with risk associated CTLA-4 +49GG allele while GAD65 induced IL-4 secretion was lower in risk subjects. Individuals with T1D neutral HLA showed higher IFN-γ responses to GAD65 than DR3-DQ2 and DR4-DQ8 positive children. We did also detect that T1D patients have reduced IFN-γ responses to GAD65 compared to healthy children. Interestingly, HLA and CTLA-4 risk genotype seem to reduce those responses to become similar to responses of T1D patients. We also found that CTLA-4 and HLA risk is associated to reduced percentages of lymphocytes expressing intracellular CTLA-4 in healthy children. In another study we recorded maintained levels of CTLA-4 and TGF-β mRNA responsiveness to GAD65 in recent onset T1D patients receiving ECP treatment although clinical outcome was certainly limited. In conclusion, HLA Class II risk genes but also CTLA-4 +49A/G to some extent, influence CTLA-4 capacity and T1D protective antigen-specific responses in a manner that might explain the genes’ predisposing and pathogenic capability.