Introduction
Rheumatoid arthritis (RA) is a chronic autoimmune arthritis leading to severe inflammation, and destruction of articular joints. Susceptibility of RA is associated with the major histocompatibility complex (MHC) class. Drugs that regulate CD4+T cell activation, such as calcineurin inhibitors and abatacept, have been shown to be effective for RA treatment; thus, CD4+T cells are a necessary component of the pathogenesis and continuity of RA1,2,3.
Differentiation of CD4+T cells into various T helper (Th) cell subsets is regulated by the expression of specific transcriptional factors. Th17 cells are a subset of Th cells that are related with the pathology of RA4,5. Retinoic acid receptor-related orphan receptor-γt (RORγt), a transcriptional factor induced in the presence of IL-6 and TGFβ, regulates IL-17 production and CC chemokine receptor 6 (CCR6) expression in CD4+ T cells, resulting in the differentiation of Th17 cells6,7,8,9. Because IL-17 produced from joint-infiltrated Th17 cells amplifies the joint inflammation through the facilitation of neutrophil migration into inflamed joints, and the expression of receptor activator of nuclear factor-κB ligand (RANKL) on Th17 cells induces bone destruction via the promotion of osteoclast differentiation, RORγt expression was suggested to play an important role in RA development10,11.
Regulatory T cells are one of the T cell subsets that regulate T cell-induced inflammation. Forkhead box P3 is transcriptional factor (Foxp3) regulates Treg cell differentiation and function through the induction of IL-10 production and cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression12. Treg cells and their specific transcription factor, Foxp3, is assumed to play an important role in suppression of RA development13,14. Recently,Th17-specific effector Treg cells, known as T regulatory 17 (Tr17) cells, have been reported to express both RORγt and Foxp3 and regulate experimental autoimmune encephalomyelitis (EAE)15. In our previous study of Collagen induced arthritis (CIA), we suggested that RORγt+Foxp3+Tr17-like cells might suppress the development of arthritis through the preferential infiltration into inflamed joints and high production of IL-10 in RORγt Tg mice16. On the other hand, RORγt+Treg cells include a subpopulation called CD25loRORγt+Treg cells, which express low levels of CD25 (unstable Foxp3 expression) and can convert to highly arthritogenic Th17 cells17. Therefore, we investigated the precise role of Tr17 cells in autoimmune arthritis. In this study, Foxp3creRORγtfl/fl mice with Tr17 cell deletion showed prolongation of more severe arthritis. Moreover, after the onset of arthritis, Tr17 cells were significantly increased in ankle joints compared with draining lymph nodes, and showed high IL-10 production. Tr17-enriched Treg cells also significantly suppressed proliferation of conventional T cells. Collectively, our study indicates the critical role of Tr17 cells in the inhibition of autoimmune arthritis aggravation thorough high expression of suppressive molecules such as IL-10 and preferential infiltration to inflamed joints.