Homeostatic signals, including IL-7 and self-MHC recognition, induce the development of peripheral helper T cells, which are enriched in the joints of rheumatoid arthritis

Ryosuke Tsurui; Hisakata Yamada; Takahiro Natori; Motoki Yoshimura; Yukio Akasaki; Shinya Kawahara; Hiroaki Niiro; Yuya Kunisaki; Yasuharu Nakashima

doi:10.1016/j.jtauto.2024.100258

Homeostatic signals, including IL-7 and self-MHC recognition, induce the development of peripheral helper T cells, which are enriched in the joints of rheumatoid arthritis

J Transl Autoimmun. 2024 Oct 30:9:100258. doi: 10.1016/j.jtauto.2024.100258. eCollection 2024 Dec.

Authors

Ryosuke Tsurui¹, Hisakata Yamada², Takahiro Natori¹, Motoki Yoshimura³, Yukio Akasaki¹, Shinya Kawahara¹, Hiroaki Niiro⁴, Yuya Kunisaki⁵, Yasuharu Nakashima¹

Affiliations

¹ Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
² Department of Clinical Immunology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
³ Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁴ Department of Medical Education, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁵ Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Abstract

Objective: Dysregulated T cell homeostasis has long been implicated in the pathogenesis of rheumatoid arthritis (RA), in the joint of which peripheral helper T (Tph) cells accumulate and form ectopic lymphoid organs. We examined whether homeostatic signals are involved in the development of Tph cells.

Methods: Human peripheral blood mononuclear cells were cultured with IL-7, the critical cytokine for T cell homeostasis. Development of Tph-like cells was assessed by flow cytometry, gene expression, and functional analysis. Chemotaxis of the Tph-like cells to RA synovial fluid (RASF) and the effect of RASF on the development of Tph-like cells was examined.

Results: PD-1^highCXCR5^- Tph-like cells developed from human peripheral blood CD4 T cells after proliferation in response to IL-7. Signals from self-MHC recognition and CD28 co-stimulation were also involved. The IL-7-induced Tph-like (IL-7-Tph) cells produced CXCL13 and IL-21 and helped B cells produce IgG. Comprehensive gene expression analysis further supported the similarity with Tph cells in RA joint. IL-7-Tph cells exhibited chemotaxis toward synovial fluid from RA patients (RASF), and RASF promoted the development of IL-7-Tph cells, which were also induced from CD4 T cells residing in non-inflamed joints.

Conclusions: Our results demonstrate an antigen-nonspecific developmental pathway of Tph cells triggered by homeostatic signals and promoted by the local environment of RA, which accounts for the accumulation of Tph cells in inflamed joints.

Keywords: Interleukin-7; Peripheral helper T cells; Rheumatoid arthritis.