CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue

Feng Liu¹, Hui Shi¹, Jason D Turner², Rachel Anscombe³, Jiaqi Li¹, Takuya Sekine⁴, Ariane Hammitzsch⁵, Devika Agarwal³, Christopher Mahony⁶, Jiewei Chen⁷, Ben Kendrick⁸, Dajiang Du⁷, Qiang Tong⁹, Lihua Duan¹⁰, Kyla Dooley¹¹, Hai Fang¹², Ilya Korsunsky¹³, Roopa Madhu¹³, Adam P Cribbs¹⁴; Cartography Consortium; Matthias Friedrich¹⁵, Brian D Marsden¹⁶, Yi-Ling Chen¹⁷, Graham Ogg¹⁸, Anna Adams¹⁹, Warner Chen²⁰, Steven Leonardo²⁰, Fiona E McCann³, Christopher D Buckley³, Terence Rooney²⁰, Thomas Freeman²⁰, Holm H Uhlig²¹, Calliope Dendrou³, Adam Croft⁶, Andrew Filer⁶, Paul Bowness¹, Liye Chen²²

Affiliations

¹ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
² Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.
³ Kennedy Institute of Rheumatology, Old Road Campus, University of Oxford, Oxford, United Kingdom.
⁴ Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
⁵ TUM University Hospital, Klinikum Rechts der Isar, Department of Nephrology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany.
⁶ Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom; NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom.
⁷ Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.
⁸ Nuffield Orthopaedic Centre, Oxford University Hospitals Trust, Oxford, United Kingdom; Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Science, University of Oxford, Oxford, United Kingdom.
⁹ Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Division of Rheumatology and Clinical Immunology, Department of Medicine, Queen Mary Hospital, Hong Kong, China.
¹⁰ Department of Rheumatology and Clinical Immunology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China.
¹¹ Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom.
¹² Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
¹³ Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
¹⁴ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom; Oxford Translational Myeloma Centre (OTMC), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
¹⁵ Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom; Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
¹⁶ Centre for Medicines Discovery & Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁷ MRC Translational Immune Discovery Unity, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK.
¹⁸ Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; MRC Translational Immune Discovery Unity, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁹ Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
²⁰ Janssen Research & Development, LLC, Spring House, PA, USA.
²¹ Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom; Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK.
²² Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom. Electronic address: liyechen2009@gmail.com.

PMID: 40413112
DOI: 10.1016/j.ard.2025.04.018

Free article

CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue

Feng Liu et al. Ann Rheum Dis. 2025 Jul.

Free article

. 2025 Jul;84(7):1151-1163.

doi: 10.1016/j.ard.2025.04.018. Epub 2025 May 24.

Authors

Affiliations

¹ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
² Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.
³ Kennedy Institute of Rheumatology, Old Road Campus, University of Oxford, Oxford, United Kingdom.
⁴ Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
⁵ TUM University Hospital, Klinikum Rechts der Isar, Department of Nephrology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany.
⁶ Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom; NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom.
⁷ Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.
⁸ Nuffield Orthopaedic Centre, Oxford University Hospitals Trust, Oxford, United Kingdom; Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Science, University of Oxford, Oxford, United Kingdom.
⁹ Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Division of Rheumatology and Clinical Immunology, Department of Medicine, Queen Mary Hospital, Hong Kong, China.
¹⁰ Department of Rheumatology and Clinical Immunology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China.
¹¹ Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom.
¹² Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
¹³ Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
¹⁴ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom; Oxford Translational Myeloma Centre (OTMC), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
¹⁵ Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom; Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
¹⁶ Centre for Medicines Discovery & Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁷ MRC Translational Immune Discovery Unity, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK.
¹⁸ Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; MRC Translational Immune Discovery Unity, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁹ Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
²⁰ Janssen Research & Development, LLC, Spring House, PA, USA.
²¹ Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom; Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK.
²² Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom. Electronic address: liyechen2009@gmail.com.

PMID: 40413112
DOI: 10.1016/j.ard.2025.04.018

Abstract

Objectives: Interleukin (IL)-17A is a key driver of spondyloarthritis (SpA) joint pathology. We aimed to identify its cellular source in synovial tissue from patients with 2 forms of SpA, namely axial SpA (AxSpA) and psoriatic arthritis (PsA).

Methods: Synovial tissue from patients with SpA was profiled using single-cell RNA sequencing (scRNA-seq; AxSpA, n = 5; PsA, n = 6) or spatial RNA profiling (PsA, n = 4). CellPhoneDB was used to infer cell-cell communication. Tissue-resident memory Th17 (TRM17)-like cells were generated in vitro using blood memory CD4+ T cells from SpA patients. An epigenetic inhibitor library, siRNA, and clustered regularly interspaced short palindromic repeats (CRISPR) were used to identify epigenetic regulator(s) for TRM17.

Results: scRNA-seq showed that CD4+CXCR6+ TRM17 cells are the predominant spontaneous IL17A producers in SpA synovium. Cell-cell communication and single-cell spatial analysis support the interaction between TRM17 and CLEC10A+ dendritic cells, which were activated in SpA. Both sublining and lining fibroblasts in SpA synovium showed evidence of interleukin (IL)-17A activation. In vitro-generated CD4+ TRM17-like cells phenocopied joint tissue TRM17, producing IL-17A/F upon T cell-receptor (TCR) stimulation, which was further enhanced by cytokines. Perturbation of BRD1 inhibited the generation of TRM17-like cells.

Conclusions: CD4+ TRM17 cells are the predominant source of IL-17A in SpA synovial tissue. TCR stimulation is essential for the secretion of IL-17A by CD4+TRM17-like cells. The epigenetic regulator bromodomain-containing protein 1 (BRD1) contributes to the generation of CD4+TRM17. Depleting CD4+TRM17 cells in SpA is thus a therapeutic strategy with potential to induce long-term remission.

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Conflict of interest statement

Competing interests This work has been partially funded by J&J to the Cartography Consortium. LC has received research support from Novartis. PB has received research support from Regeneron, Benevolent AI, Novartis, and GSK. HHU has received research support or consultancy fees from J&J, UCB Pharma, Eli Lilly, BMS Celgene, and GSK. Liye Chen reports financial support was provided by J&J. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue

Affiliations

CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue

Authors

Affiliations

Abstract

Conflict of interest statement

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Full Text Sources

Medical

Research Materials

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