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

Abstract

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.