Maternal Type 1 Diabetes Reduces Autoantigen-Responsive CD4+ T Cells in Offspring

Autoimmunity against pancreatic β-cell autoantigens is a characteristic of childhood type 1 diabetes. Autoimmunity usually appears in genetically susceptible children with the development of autoantibodies against (pro)insulin in early childhood. The offspring of mothers with type 1 diabetes are protected from this process. The aim of this study was to determine whether the protection conferred by maternal type 1 diabetes is associated with improved neonatal tolerance against (pro)insulin. Consistent with improved neonatal tolerance, the offspring of mothers with type 1 diabetes had reduced cord blood CD4+ T cell responses to proinsulin and insulin, a reduction in the inflammatory profile of their proinsulin-responsive CD4+ T cells, and improved regulation of CD4+ T cell responses to proinsulin at 9 months of age, as compared with offspring with a father or sibling with type 1 diabetes. Maternal type 1 diabetes was also associated with a modest reduction in CpG methylation of the INS gene in cord blood mononuclear cells from offspring with a susceptible INS genotype. Our findings support the concept that a maternal type 1 diabetes environment improves neonatal immune tolerance against the autoantigen (pro)insulin.