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

• Main Authors: Sudeep Chenna Narendra, Jaya Prakash Chalise, Sophie Biggs, Ulrich Kalinke, Mattias Magnusson
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2018-02-01
• Series: Frontiers in Immunology
• Subjects: interferon-alpha; regulatory T-cells; experimental arthritis; indoleamine 2,3-dioxygenase; kynurenine
• Online Access: http://journal.frontiersin.org/article/10.3389/fimmu.2018.00285/full

ObjectiveCD4+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.MethodsArthritis 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.ResultsBoth 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.ConclusionBy 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.