Stem-like and effector peripheral helper T cells comprise distinct subsets in rheumatoid arthritis
Peripheral helper T (T<sub>PH</sub>) cells can play pathogenic roles in human autoimmune diseases. T<sub>PH</sub> cells are proposed to be the major B cell helpers in inflamed joints in rheumatoid arthritis (RA), but whether and how T<sub>PH</sub> cells are engaged in tissue inflammation remains unclear. We demonstrate that T<sub>PH</sub> cells comprise two subsets in RA: stem-like T<sub>PH</sub> (S-T<sub>PH</sub>) and effector T<sub>PH</sub> (E-T<sub>PH</sub>) cells. These two subsets differed in transcriptome, epigenome, B cell helper capacity, spatial localization, and cell interactions. S-T<sub>PH</sub> cells displayed self-renewal capacity and were mainly found within tertiary lymphoid structures (TLSs) in synovial tissue together with B cells. S-T<sub>PH</sub> cells potently induced B cells to produce immunoglobulins. By contrast, E-T<sub>PH</sub> cells expressed effector molecules and colocalized with proinflammatory macrophages and CD8<sup>+</sup> T cells outside TLSs. S-T<sub>PH</sub> cells could differentiate into E-T<sub>PH</sub> cells upon TCR stimulation and coculture with B cells. Collectively, our study shows that S-T<sub>PH</sub> cells play a central role in promoting T<sub>PH</sub> responses by undergoing self-renewal and seeding E-T<sub>PH</sub> cells.
Authors
- Chikashi C. Terao (ORCID: https://orcid.org/0000-0002-6452-4095)
- Yasuhiro Murakawa (ORCID: https://orcid.org/0000-0002-5415-1352)
- Akinori Murakami (ORCID: https://orcid.org/0009-0002-4666-5326)
- Osamu Iri
- Yugo Morita (ORCID: https://orcid.org/0000-0001-7674-1815)
- Yukinori Okada (ORCID: https://orcid.org/0000-0002-0311-8472)
- Motomu Hashimoto (ORCID: https://orcid.org/0000-0002-9241-060X)
- Kohei Nishitani (ORCID: https://orcid.org/0000-0002-8327-3826)
- Hideki Ueno (ORCID: https://orcid.org/0000-0001-7747-0738)
- Yuki Masuo (ORCID: https://orcid.org/0009-0007-3515-173X)
- Koichi Murata (ORCID: https://orcid.org/0000-0002-7896-3937)
- Hiroyuki Yoshitomi (ORCID: https://orcid.org/0000-0001-7339-9030)
- Hiromu Ito (ORCID: https://orcid.org/0000-0002-1827-382X)
- Shinichi Kuriyama (ORCID: https://orcid.org/0000-0003-2526-2974)
- Shinichiro Nakamura (ORCID: https://orcid.org/0000-0003-1308-7080)
- Takeshi Iwasaki (ORCID: https://orcid.org/0000-0002-9326-3699)
- Ryu Watanabe (ORCID: https://orcid.org/0000-0002-1089-5296)
- Takayuki Fujii (ORCID: https://orcid.org/0000-0002-6556-1226)
- Shunsuke Uno (ORCID: https://orcid.org/0000-0002-5797-694X)
- Shuichi Matsuda (ORCID: https://orcid.org/0000-0003-0802-1255)
- Rinko Akamine
Institutions
- University of Shizuoka (JP)
- Kyoto University (JP)
- Kurashiki Central Hospital (JP)
- Shizuoka General Hospital (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- Osaka Metropolitan University (JP)
- The University of Tokyo (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1126/sciimmunol.adt3955
- Citations
- 5
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 3.99