Stem-like Peripheral Helper T Cells Seed Their Effector Counterpart in Rheumatoid Arthritis

Akinori Murakami – Kyoto University; Rinko Akamine – Kyoto University; Osamu Iri – Kyoto University; Shunsuke Uno – Kyoto University; Koichi Murata – Kyoto University; Kohei Nishitani – Kyoto University; Hiromu Ito – Kyoto University; Ryu Watanabe – Osaka Metropolitan University; Takayuki Fujii – Kyoto University; Takeshi Iwasaki – Kyoto University; Shinichiro Nakamura – Kyoto University; Shinichi Kuriyama – Kyoto University; Yugo Morita – Kyoto University; Yasuhiro Murakawa – Kyoto University; Chikashi Terao – RIKEN Center for Integrative Medical Sciences; Yukinori Okada – RIKEN Center for Integrative Medical Sciences; Motomu Hashimoto – Osaka Metropolitan University; Shuichi Matsuda – Kyoto University; Hideki Ueno – Kyoto University; Hiroyuki Yoshitomi – Kyoto University

Abstract Text: Peripheral helper T (Tph) cells play important pathogenic roles in human autoimmune diseases. Tph cells are proposed to be the major B-cell helpers in inflamed joints of rheumatoid arthritis (RA). However, whether and how Tph cells are engaged in tissue inflammation remains unclear. Here, we demonstrate that Tph cells consist of two directly related subsets in RA: stem-like Tph (S-Tph) and effector Tph (E-Tph) cells. These two subsets differed in transcriptome, epigenome, B-helper capacity, spatial localization, and the encountering cells. S-Tph cells were endowed with a self-renewal capacity, which was dependent on TCF1. S-Tph cells were mainly found at the center of tertiary lymphoid structures (TLSs) and colocalized with B cells. S-Tph cells potently induced B cells to produce immunoglobulins. S-Tph cells expressed CCR7 and were in proximity to CCL19+ perivascular fibroblast-like synoviocytes in TLSs. By contrast, E-Tph cells highly expressed effector molecules including IFN-g. E-Tph cells expressed CXCR6, CCR2, and CCR5, and CXCL16+ proinflammatory macrophages and CCL4+ CCL5+ CD8+ T cells likely promoted E-Tph cells migrating outside TLSs. S-Tph and E-Tph cells robustly shared TCR clonotypes, and S-Tph cells were able to differentiate into E-Tph cells upon TCR stimulation and coculture with B cells, but not the opposite. Collectively, our study shows that S-Tph cells play a central role in promoting Tph responses by undergoing self-renewal and seeding E-Tph cells. Our study provides a rationale to target S-Tph cells for the treatment of human autoimmune diseases with an expectation to reduce global Tph responses and TLS formation.