Regulatory T-Cells Mediate IFN-?-Induced Resistance against Antigen-Induced Arthritis.

ABSTRACT:

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-?.

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-? 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^+highCD4⁺ 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-?. Depletion of T_regs in the arthritis phase, but not at immunization, abolished the protective effect of IFN-? and kynurenine against arthritis. IFN-? increased the number of T_regs in ex vivo cultures upon antigen recall stimulation but not in naïve cells. IFN-? 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-? was clearly reduced by in vivo inhibition of IDO at immunization, which also abolished the protective effect of IFN-? against arthritis.

Conclusion

By activating IDO during antigen sensitization, IFN-? activates T_regs, which prevent arthritis triggered by antigen rechallenge. This is one way by which IFN-? suppresses inflammation.

SUBMITTER: Chenna Narendra S 

PROVIDER: S-EPMC5826073 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature