Type I interferons induce peripheral T regulatory cell differentiation under tolerogenic conditions.

The type I interferons (type I IFNs) 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 IFNα/β 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 (Tregs) 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 IFNs in maintaining the function of thymus-derived Tregs has been previously described, the direct contribution of these innate factors to peripheral Treg (pTreg) and induced Treg (iTreg) differentiation and suppressive function is still unclear. We now show that, under tolerogenic conditions, IFNα/β play a critical role in antigen-specific and also polyclonal naïve CD4 + T cell conversion into peripheral antigen-specific CD4 +CD25 +Foxp3 + Tregs and inhibit CD4 + T helper (Th) cell expansion in mice. While type I IFNs sustain the expression and the activation of the transcription master regulators Foxp3, Stat3 and Stat5, these innate molecules reciprocally inhibit Th17 cell differentiation. Altogether, these results indicate a new pivotal role of IFNα/β on pTreg differentiation and induction of peripheral tolerance, which may have important implications in the therapeutic control of inflammatory disorders, such as of autoimmune diseases.

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