Journal article
CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue
- Abstract:
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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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Supplementary materials, zip, 12.7MB, Terms of use)
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(Preview, Version of record, pdf, 3.7MB, Terms of use)
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- Publisher copy:
- 10.1016/j.ard.2025.04.018
- Publication website:
- https://pure-oai.bham.ac.uk/ws/files/269447935/1-s2.0-S0003496725009070-main.pdf
Authors
+ Medical Research Council
More from this funder
- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/V010182/1
- Publisher:
- Elsevier
- Journal:
- Annals of the Rheumatic Diseases More from this journal
- Volume:
- 84
- Issue:
- 7
- Pages:
- 1151-1163
- Place of publication:
- United States
- Publication date:
- 2025-05-23
- Acceptance date:
- 2025-04-17
- DOI:
- EISSN:
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1468-2060
- ISSN:
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0003-4967
- Pmid:
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40413112
- Language:
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English
- Keywords:
- Pubs id:
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2126197
- Local pid:
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pubs:2126197
- Source identifiers:
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W4410634729
- Deposit date:
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2025-07-31
- ARK identifier:
Terms of use
- Copyright holder:
- Liu et al.
- Copyright date:
- 2025
- Rights statement:
- © 2025 The Author(s). Published by Elsevier B.V. on behalf of European Alliance of Associations for Rheumatology (EULAR). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
- Licence:
- CC Attribution (CC BY)
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