T <sub>H</sub> 17 cells converted into exT <sub>H</sub> 17 cells sustain rheumatoid-like IL-17–independent inflammatory arthritis
T helper 17 (T<sub>H</sub>17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17-targeted interventions have limited efficacy in established RA. Inflammation can induce T<sub>H</sub>17 cell transdifferentiation into IL-17-negative exT<sub>H</sub>17 cells, but the role of exT<sub>H</sub>17 cells in arthritis is unknown. We performed T<sub>H</sub>17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial T<sub>H</sub>17 cells transdifferentiate into CD44<sup>+</sup> exT<sub>H</sub>17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exT<sub>H</sub>17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4<sup>+</sup> T cells. We demonstrate that cross-talk between T<sub>H</sub>17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes T<sub>H</sub>17-exT<sub>H</sub>17 cell conversion. CD44 is necessary for exT<sub>H</sub>17 cell-mediated arthritis. Our study suggests that FLS expansion during RA progression promotes T<sub>H</sub>17-exT<sub>H</sub>17 cell conversion. These results could potentially enable RA precision therapy.
Authors
- Paramita Dutta (ORCID: https://orcid.org/0000-0003-2590-6231)
- Arthur M. Mandelin
- Francesca Ingegnoli (ORCID: https://orcid.org/0000-0002-6727-1273)
- Kensuke Suga (ORCID: https://orcid.org/0000-0003-3107-788X)
- Kathleen Aren (ORCID: https://orcid.org/0000-0003-4770-2643)
- David A. McBride (ORCID: https://orcid.org/0000-0001-7695-5178)
- Carla M. Cuda (ORCID: https://orcid.org/0000-0002-2022-8171)
- Mary Carns (ORCID: https://orcid.org/0000-0002-5063-156X)
- Nunzio Bottini (ORCID: https://orcid.org/0000-0001-9025-7501)
- Roberto Caporali (ORCID: https://orcid.org/0000-0001-6331-8559)
- Harris Perlman (ORCID: https://orcid.org/0000-0003-4174-608X)
- Jason H. Moore (ORCID: https://orcid.org/0000-0002-5015-1099)
- Ferhat Ay (ORCID: https://orcid.org/0000-0002-0708-6914)
- Katarzyna Dobaczewska (ORCID: https://orcid.org/0000-0002-6377-018X)
- Zbigniew Mikulski (ORCID: https://orcid.org/0000-0002-1918-9216)
- Sanaz Panahandeh (ORCID: https://orcid.org/0000-0001-9253-4891)
- Kyoung‐Jae Won (ORCID: https://orcid.org/0000-0002-2924-9630)
- Salina Dominguez (ORCID: https://orcid.org/0009-0002-2659-7610)
- Pietro Simone Randelli (ORCID: https://orcid.org/0000-0001-9331-820X)
- Mohammad Daud Khan
- Deborah R. Winter (ORCID: https://orcid.org/0000-0003-1806-673X)
- Angela Denn (ORCID: https://orcid.org/0000-0002-1844-4668)
- Hyobin Kim (ORCID: https://orcid.org/0000-0002-4856-7415)
- Amara Seng (ORCID: https://orcid.org/0000-0001-7077-5969)
- Nisarg J. Shah
- Mattias N. D. Svensson (ORCID: https://orcid.org/0000-0001-8077-9824)
- Martina Zoccheddu (ORCID: https://orcid.org/0000-0003-1631-0866)
- Hadijat M. Makinde (ORCID: https://orcid.org/0000-0001-8492-4187)
- Myungja Ro
- Zhiping Wang (ORCID: https://orcid.org/0000-0002-3796-3164)
- Yizhou Wang (ORCID: https://orcid.org/0000-0002-9378-745X)
- Ruth Minsha
- John F. Seagrist (ORCID: https://orcid.org/0009-0000-3629-1530)
Institutions
- Northwestern University (US)
- Cedars-Sinai Medical Center (US)
- La Jolla Institute for Immunology (US)
- University of Milan (IT)
- University of California San Diego (US)
- Istituto Ortopedico Gaetano Pini (IT)
- University of Gothenburg (SE)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-11-07
- DOI
- https://doi.org/10.1126/sciimmunol.adm7800
- Citations
- 1
- Primary Topic
- Psoriasis: Treatment and Pathogenesis
- Type
- article
- Field-Weighted Citation Impact
- 0.80