Autoreactivity of peripheral helper t cells in the joints of rheumatoid arthritis

Takahide Sakuragi, Hisakata Yamada, Akihisa Haraguchi, Kazuhiro Kai, Jun Ichi Fukushi, Satoshi Ikemura, Yukio Akasaki, Toshifumi Fujiwara, Hidetoshi Tsushima, Tomoko Tsutsui, Masakazu Kondo, Yasunobu Yoshikai, Seiji Okada, Yasuharu Nakashima

Research output: Contribution to journalArticlepeer-review

Abstract

Autoreactive CD4 T cells are thought to play pivotal roles in the pathogenesis of rheumatoid arthritis (RA). Recently, a subset of CD4 T cells that express high levels of programmed death-1 (PD-1) but are distinct from follicular helper T cells have been identified in the joints of RA patients and named peripheral helper T (Tph) cells. Because PD-1 is expressed on T cells chronically stimulated with the Ags, we tested a hypothesis that Tph cells are the pathogenic autoreactive CD4 T cells in RA. We found that human Tph cells in RA joints produce proinflammatory effector cytokines, including IFN-γ, TNF-α, and GM-CSF, in addition to B cell-helping cytokines, such as IL-21 and CXCL13. Flow cytometric analysis showed different bias of TCR Vβ usage between PD-1high Tph cells and PD-1low/neg CD4 T cells, including Th1 cells, in the joint or memory CD4 T cells in the peripheral blood, whereas there was little difference between the latter two subsets. In line with this, deep sequencing of TCR demonstrated an overlap of expanded clones between peripheral blood memory CD4 T cells and PD-1low/neg CD4 T cells but not Tph cells in the joint. Interestingly, Tph cells preferentially exhibited autologous MLR in vitro, which required recognition of self-MHC class II and was pronounced by blocking PD-1 signaling. Taken together, these results suggest that Tph cells are the pathogenic autoreactive CD4 T cells in RA, which expand locally in the joints and are regulated by PD-1 signaling.

Original languageEnglish
Pages (from-to)2045-2051
Number of pages7
JournalJournal of Immunology
Volume206
Issue number9
DOIs
Publication statusPublished - May 1 2021

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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