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.