Type I Interferons Induce Peripheral T Regulatory Cell Differentiation Under Tolerogenic Conditions

The type I interferons are central to a vast array of immunological functions.The production of these immune-modulatory molecules is initiated at the early stages of the innate immune responses and, therefore, plays a dominant role in shaping downstream events in both innate and adaptive immunity. Indeed, the major role of IFN-alpha/beta is the induction of priming states, relevant for the functional differentiation of T lymphocyte subsets. Among T-cell subtypes, the CD4(+)CD25(+)Foxp3(+) T regulatory cells (T-regs) represent a specialized subset of CD4(+) T cells with a critical role in maintaining peripheral tolerance and immune homeostasis. Although the role of type I interferons in maintaining the function of thymus-derived T-regs has been previously described, the direct contribution of these innate factors to peripheral T-reg (pT(reg)) and induced T-reg(iT(reg)) differentiation and suppressive function is still unclear. We now show that, under tolerogenic conditions, IFN-alpha/beta play a critical role in antigen-specific and also polyclonal naive CD4(+)-T-cell conversion into peripheral antigen-specific CD4(+)CD25(+)Foxp3(+)T(regs) and inhibit CD4(+)T helper (T-h) cell expansion in mice. While type I interferons sustain the expression and the activation of the transcription master regulators Foxp3, Stat3 and Stat5, these innate molecules reciprocally inhibit T(h)17 cell differentiation. Altogether, these results indicate a new pivotal role of IFN-alpha/beta on pT(reg) differentiation and induction of peripheral tolerance, which may have important implications in the therapeutic control of inflammatory disorders, such as of autoimmune diseases.