CD4+CD45RA−FoxP3high activated regulatory T cells are functionally impaired and related to residual insulin‐secreting capacity in patients with type 1 diabetes

Accumulating lines of evidence have suggested that regulatory T cells (T_regs) play a central role in T cell-mediated immune response and the development of type 1A and fulminant type 1 diabetes. CD4⁺forkhead box protein 3 (FoxP3)⁺ T cells are composed of three phenotypically and functionally distinct subpopulations; CD45RA⁺FoxP3^low resting T_regs (r-T_regs), CD45RA⁻FoxP3^high activated T_regs (a-T_regs) and CD45RA⁻FoxP3^low non-suppressive T cells (non-T_regs). We aimed to clarify the frequency of these three subpopulations in CD4⁺FoxP3⁺ T cells and the function of a-T_regs with reference to subtypes of type 1 diabetes. We examined 20 patients with type 1A diabetes, 15 patients with fulminant type 1 diabetes, 20 patients with type 2 diabetes and 30 healthy control subjects. A flow cytometric analysis in the peripheral blood was performed for the frequency analysis. The suppressive function of a-T_regs was assessed by their ability to suppress the proliferation of responder cells in a 1/2:1 co-culture. A flow cytometric analysis in the peripheral blood demonstrated that the frequency of a-T_regs was significantly higher in type 1A diabetes, but not in fulminant type 1 diabetes, than the controls. Further, the proportion of a-T_regs among CD4⁺FoxP3⁺ T cells was significantly higher in patients with type 1A diabetes with detectable C-peptide but not in patients with type 1A diabetes without it and with fulminant type 1 diabetes. A proliferation suppression assay showed that a-T_regs were functionally impaired both in fulminant type 1 diabetes and in type 1A diabetes. In conclusion, a-T_regs were functionally impaired, related to residual insulin-secreting capacity and may be associated with the development of type 1 diabetes.