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

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.