Control of the differentiation of Foxp3+ regulatory T cells suppressing the development of auoimmune arthritis

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08877
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: University of Tsukuba
• Principal Investigator: Kondo Yuya 筑波大学, 医学医療系, 講師 (40612487)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 関節リウマチ / 制御性T細胞 / 転写因子 / サイトカイン / ケモカイン / Foxp3 / RORγt / IL-10

Outline of Final Research Achievements

RORγt+Foxp3+ regulatory T cells (Tregs), known as Tr17 cells, have the potential to suppress Th17 cell mediated inflammation. The aim of this study is to elucidate the role of Tr17 cells in rheumatoid arthritis (RA). In murine model of RA, arthritis was found to be prolonged in Foxp3creRORγtfl/fl mice, in which Tr17 cells were deleted, compared with control mice. Tr17 cells significantly accumulated in inflamed joints after the onset of arthritis with up-regulation of CCR6. Tr17 cells also highly produced IL-10, and had the potential to suppress the proliferation of effector CD4+ T cells. In human peripheral blood, CXCR3-CCR6+ Th17-like Tregs had the highest RORγt expression, suggesting a similarity between Th17-like Tregs and Tr17 cells. Effector Th17-like Tregs were the only subset significantly decreased in patients with RA, and negatively correlated with DAS28-ESR.
Our results indicated the possibility that Tr17 cells might specifically regulate the pathogenesis of RA.

Free Research Field

リウマチ性疾患

Academic Significance and Societal Importance of the Research Achievements

これまでの様々な知見から、制御性T細胞（Treg）は関節リウマチ（RA）の疾患形成に本質的に関与していることが推測されるが、その詳細は明らかになっておらず、臨床応用に足るだけの研究成果が得られていない状況であった。本研究ではRORγtを発現したTregサブセットであるTr17細胞に注目し、マウスのRAモデル、さらにはRA患者検体を用いた解析を実施し、Tr17細胞がRAによってもたらされる関節炎を特異的に制御する可能性があることを見出した。本検討を契機として、TregによるRAの関節炎制御機構の詳細が明らかになれば、RAの病態を根本的に制御する新しい治療戦略の創生につながることが期待される。