CD147 Expressed on Memory CD4+ T Cells Limits Th17 Responses in Patients With Rheumatoid Arthritis.

Jinlin Miao,Kui Zhang,Zhinan Chen,Rui Zhang,Qing Han,Na Guo,Minghua Lv,Yingming Xu,Ping Zhu,Zhaohui Zheng

doi:10.3389/fimmu.2020.545980

Jinlin Miao, Kui Zhang + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2020.545980

Copy DOI

Abstract

Rheumatoid arthritis (RA) is a common autoimmune disease in which T helper-type 17 (Th17) cells have been critically involved. CD147 is a T cell activation-associated molecule and is involved in T cell development. However, it remains unclear whether CD147 participates in Th17 responses in RA patients. In this study, we demonstrated that in both the RA and healthy controls (HC) groups, CD147 expression on CD4+ T cells was increased in CCR6+ and CD161+ subsets, and was associated with IL-17 production. Ligation of CD147 with its monoclonal antibody (mAb) strongly inhibited Th17 responses, and knock down of CD147 expression on CD4+ Tm cells specifically enhanced Th17 responses, triggered by coculture with in vitro activated monocytes from HC. Further functional studies showed that anti-CD147 mAb decreased the activation of AKT, mTORC1 and STAT3 signaling, which is known to enhance Th17 responses. Ligation of CD147 with its mAb on CD4+ Tm cells specifically reduced Th17 responses induced by in vitro or in vivo activated monocytes from RA patients. In collagen-induced arthritis model, anti-CD147 mAb treatment reduced the Th17 levels and severity of arthritis in vivo. These data suggest that CD147 plays a negative role in regulating human Th17 responses. Anti-CD147 mAb can limit the extraordinary proliferation of Th17 cells and may be a new therapeutic option in RA.

Highlights

Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by the infiltration of antigen-presenting cells (APCs) and T cells into the joints, synovial hyperplasia, and systemic inflammation
We provide evidence that CD147 expression was increased in IL-17–producing CD4+ T cells, which in turn acts as a negative limitation loop to suppress human Th17 responses and inhibit the generation of Th17 cells in RA
In both healthy controls (HC) and RA patients, CD147 expression on CD4+ T cells was increased in CCR6+ and CD161+ fraction

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by the infiltration of antigen-presenting cells (APCs) and T cells into the joints, synovial hyperplasia, and systemic inflammation. Th17 cells (T helper cells that produce interleukin 17 [IL-17]) are thought to promote the development and pathogenesis of RA [1,2,3]. Investigations into the mechanisms that control Th17 responses in humans are essential for a greater understanding of RA pathogenesis and therapeutics. In this regard, much has been accomplished in the last decade. Depending on signals from APCs, Th17 cells can be generated from CD4+ naïve T cells, and from CD4+ memory T

Methods

Results

Conclusion