Revisiting regulatory T cells in type 1 diabetes

Purpose of review Regulatory T cells (Treg) maintain immune homeostasis and prevent autoimmune disease. This review summarizes the recent advances in Treg knowledge relevant to type 1 diabetes, focusing on Treg signature, antigen specificity and development and function in the face of inflammation. Recent findings Thymus-derived natural regulatory T cells (nTreg) programmed by the transcription factor forkhead box P3 (FOXP3) and peripheral-induced regulatory T cells (iTreg) have largely nonoverlapping T-cell receptor repertoires to self-antigens and jointly contribute to immune homeostasis. Initial reports that CD4(+)CD25(+) (FOXP3(+)) Treg were impaired in frequency or function in type 1 diabetes have not been confirmed. The Treg-specific demethylated region in the FOXP3 locus in nTreg is, in contrast, methylated in iTreg and conventional T cells (Tconv) and is the only feature that reliably distinguishes activated human nTreg and Tconv. Inflammatory cytokines regulate extrathymic differentiation of nTreg but can also reprogram nTreg into Th17 or Th1 effectors and prevent the differentiation of iTreg. Summary The methylation status of the FOXP3 locus provides a means to re-examine Treg in autoimmune disease. nTreg and iTreg recognize different self-antigens. Shaping of Treg by the cytokine milieu has implications for the application of Treg cell-based immune therapies.