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-α/ß 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 interferons 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, IFN-α/ß play a critical role in antigen-specific and also polyclonal naive 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 interferons 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 IFN-α/ß 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.

APC activation by IFN-alpha decreases regulatory T cell and enhances Th cell functions.

Type I IFNs are central to a vast array of immunological functions. Their early induction in innate immune responses provides one of the most important priming mechanisms for the subsequent establishment of adaptive immunity. The outcome is either promotion or inhibition of these responses, but the conditions under which one or the other prevails remain to be defined. The main objective of the current study was to determine the involvement of IFN-alpha on murine CD4(+)CD25(-) Th cell activation, as well as to define the role played by this cytokine on CD4(+)CD25(+) regulatory T (Treg) cell proliferation and function. Although IFN-alpha promotes CD4(+)CD25(-) Th cells coincubated with APCs to produce large amounts of IL-2, the ability of these cells to respond to IL-2 proliferative effects is prevented. Moreover, in medium supplemented with IFN-alpha, IL-2-induced CD4(+)CD25(+) Treg cell proliferation is inhibited. Notably, IFN-alpha also leads to a decrease of the CD4(+)CD25(+) Treg cell suppressive activity. Altogether, these findings indicate that through a direct effect on APC activation and by affecting CD4(+)CD25(+) Treg cell-mediated suppression, IFN-alpha sustains and drives CD4(+)CD25(-) Th cell activation.