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Regulatory T-Cells Mediate IFN-alpha-Induced Resistance against Antigen-Induced Arthritis
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Osaka Univ, Japan.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Zentrum Expt and Klin Infekt Forsch, Germany.
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2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 285Article in journal (Refereed) Published
Abstract [en]

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-alpha. 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-alpha 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-alpha. Depletion of T-regs in the arthritis phase, but not at immunization, abolished the protective effect of IFN-alpha and kynurenine against arthritis. IFN-alpha increased the number of T-regs in ex vivo cultures upon antigen recall stimulation but not in naive cells. IFN-alpha 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-alpha was clearly reduced by in vivo inhibition of IDO at immunization, which also abolished the protective effect of IFN-alpha against arthritis. Conclusion: By activating IDO during antigen sensitization, IFN-alpha activates T-regs, which prevent arthritis triggered by antigen rechallenge. This is one way by which IFN-alpha suppresses inflammation.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2018. Vol. 9, article id 285
Keywords [en]
interferon-alpha; regulatory T-cells; experimental arthritis; indoleamine 2, 3-dioxygenase; kynurenine
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-145765DOI: 10.3389/fimmu.2018.00285ISI: 000425412000001PubMedID: 29515584OAI: oai:DiVA.org:liu-145765DiVA, id: diva2:1192483
Note

Funding Agencies|Vetenskapsradet [521-2011-3095]; Reumatikerforbundet [R474951, R568881]; Ostergotland county hospital grant (ALF) [LIO-606871]

Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-04-13

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