AUTHOR=Chenna Narendra Sudeep , Chalise Jaya Prakash , Biggs Sophie , Kalinke Ulrich , Magnusson Mattias TITLE=Regulatory T-Cells Mediate IFN-α-Induced Resistance against Antigen-Induced Arthritis JOURNAL=Frontiers in Immunology VOLUME=9 YEAR=2018 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00285 DOI=10.3389/fimmu.2018.00285 ISSN=1664-3224 ABSTRACT=Objective

CD4+FoxP3+CD25+ regulatory T-cells (Tregs) are important for preventing tissue destruction. Here, we investigate the role of Tregs 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 Tregs 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. Tregs were depleted in DT-treated Foxp3DTReGFP+/− mice and enumerated by FoxP3 staining. Suppressive capacity of FACS-sorted CD25+highCD4+ Tregs 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 Tregs 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 Tregs in ex vivo cultures upon antigen recall stimulation but not in naïve cells. IFN-α also increased the suppressive capacity of Tregs 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 Tregs, which prevent arthritis triggered by antigen rechallenge. This is one way by which IFN-α suppresses inflammation.