1,25-Dihydroxyvitamin D3 and Its Analog TX527 Promote a Stable Regulatory T Cell Phenotype in T Cells from Type 1 Diabetes Patients

The emergence of regulatory T cells (Tregs) as central mediators of peripheral tolerance in the immune system has led to an important area of clinical investigation to target these cells for the treatment of autoimmune diseases such as type 1 diabetes. We have demonstrated earlier that in vitro treatment of T cells from healthy individuals with TX527, a low-calcemic analog of bioactive vitamin D, can promote a CD4(+)CD25(high)CD127(low) regulatory profile and imprint a migratory signature specific for homing to sites of inflammation. Towards clinical application of vitamin D-induced Tregs in autologous adoptive immunotherapy for type 1 diabetes, we show here that 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] and TX527 similarly imprint T cells from type 1 diabetes patients with a CD4(+)CD25(high)CD127(low) regulatory profile, modulate surface expression of skin- and inflammation-homing receptors, and increase expression of CTLA-4 and OX-40. Also, 1,25(OH)(2)D-3 and TX527 treatment inhibit the production of effector cytokines IFN-gamma, IL-9, and IL-17. Importantly, 1,25(OH)(2)D-3 and TX527 promote the induction of IL-10-producing CD4(+)CD25(high)CD127(low) T cells with a stable phenotype and the functional capacity to suppress proliferation of autologous responder T cells in vitro. These findings warrant additional validation of vitamin D-induced Tregs in view of future autologous adoptive immunotherapy in type 1 diabetes.