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Objective  CD4 + FoxP3 + CD25 +  regulatory T-cells (T regs ) are important for preventing tissue destruction. Here, we investigate the role of T regs  for protection against experimental arthritis by IFN-α.    Methods  Arthritis was triggered by intra-articular injection of methylated bovine serum albumin (mBSA) in wild-type mice, Foxp3DTReGFP +/−  mice [allowing selective depletion of T regs  by diphtheria toxin (DT)] and CD4-Cre +/−  IFNA1R flox/flox mice (devoid of IFNAR signaling in T-cells) earlier immunized with mBSA, with or without treatment with IFN-α or the indoleamine 2,3-dioxygenase (IDO)-metabolite kynurenine. T regs  were depleted in DT-treated Foxp3DTReGFP +/−  mice and enumerated by FoxP3 staining. Suppressive capacity of FACS-sorted CD25 +high CD4 +  T regs  was tested  in vivo  by adoptive transfer and  ex vivo  in cocultures with antigen-stimulated CFSE-stained T-responder (CD25 − CD4 + ) cells. IDO was inhibited by 1-methyl tryptophan.    Results  Both control mice and mice devoid of IFNAR-signaling in T helper cells were protected from arthritis by IFN-α. Depletion of T regs  in the arthritis phase, but not at immunization, abolished the protective effect of IFN-α and kynurenine against arthritis. IFN-α increased the number of T regs  in  ex vivo  cultures upon antigen recall stimulation but not in naïve cells. IFN-α also increased the suppressive capacity of T regs  against mBSA-induced T-responder cell proliferation  ex vivo  and against arthritis when adoptively transferred. The increased suppressive activity against proliferation conferred by IFN-α was clearly reduced by  in vivo  inhibition of IDO at immunization, which also abolished the protective effect of IFN-α against arthritis.    Conclusion  By activating IDO during antigen sensitization, IFN-α activates T regs , which prevent arthritis triggered by antigen rechallenge. This is one way by which IFN-α suppresses inflammation.

Regulatory T-Cells Mediate IFN-α-Induced Resistance against Antigen-Induced Arthritis