The effects of maternal type 1 diabetes on autoreactive CD4+ T cells in neonates

The risk of developing type 1 diabetes is decreased in children born to mothers with type 1 diabetes as compared to children with a father or sibling with type 1 diabetes. We hypothesized that protection is provided by the increased proinsulin and insulin production by the fetus during a maternal type 1 diabetes pregnancy via an increased efficiency of (pro)insulin-specific T cell removal and regulation. To test this, CD4⁺ T cell responses to proinsulin and insulin were examined at birth in children who had a father or sibling with type 1 diabetes (n=14), a mother with type 1 diabetes (n=15) or without a first degree family history of type 1 diabetes (n=16). Multi-parametric flow cytometry analysis identified increased hematopoietic stem cell numbers in cord blood from children with diabetic mothers (p=0.002). The frequencies of responding CD4⁺ T cells to proinsulin (p=0.0046) and to insulin (p=0.0009) were increased in neonates with fathers or siblings with type 1 diabetes as compared to neonates of non-diabetic parents and to neonates with mothers with type 1 diabetes (p=0.0027 and 0.0046). Single cell gene expression profiling of proinsulin-responsive CD4⁺ T cells at birth showed reduced Th1 and Th17 profiles (CTLA4, p p<0.0001; CCR3, p<0.0001; CCR5, p=0.0001; CCR6, p=0.0008; AHR, p=0.0008 and RORA, p=0.0009) in neonates of mothers with type 1 diabetes compared to children with a father or sibling with T1D. In samples taken after birth, the ability of T_reg cells to suppress proinsulin-specific CD4+ T cells was increased in children of mothers with type 1 diabetes compared to children with another first degree T1D patient (p=0.0016). These findings suggest that increased (pro)insulin production by the fetus during maternal type 1 diabetes gestation favors central and peripheral tolerance to these key targets of autoimmunity in type 1 diabetes.