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

Liu, F; Shi, H; Turner, JD; Anscombe, R; Li, J; Sekine, T; Hammitzsch, A; Agarwal, D; Mahony, C; Chen, J; Kendrick, B; Du, D; Tong, Q; Duan, L; Dooley, K; Fang, H; Korsunsky, I; Madhu, R; Cribbs, AP; Cartography Consortium; Friedrich, M; Marsden, BD; Chen, YL; Ogg, G; Adams, A; Chen, W; Leonardo, S; McCann, FE; Buckley, CD; Rooney, T; Freeman, T; Uhlig, HH; Dendrou, C; Croft, A; Filer, A; Bowness, P; Chen, L

doi:10.1016/j.ard.2025.04.018

Spondyloarthritis & psoriatic arthritis

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

Ann Rheum DisPublished 24 May 2025Mechanistic study

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Authors' conclusion

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.

Study context

Population: Patients with spondyloarthritis (SpA) (axial SpA (AxSpA) and psoriatic arthritis (PsA)): synovial tissue; blood memory CD4+ T cells for in vitro work
Participants: 5 / 6 / 4

Comparison: AxSpA vs PsA vs PsA (spatial)
AxSpAn = 5
PsAn = 6
PsA (spatial)n = 4
Outcome: Cellular source of IL-17A in SpA synovial tissue

Methodological detailssingle-cell RNA sequencing, spatial RNA profiling, in vitro TRM17-like cell generation, epigenetic inhibitor library, siRNA and clustered regularly interspaced short palindromic repeats (CRISPR) screening

Single-cell RNA sequencing
Spatial RNA profiling
In vitro TRM17-like cell generation
Epigenetic inhibitor library, siRNA and CRISPR screening

Main finding

As reported in the abstract

Cellular source of IL-17A in SpA synovium

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

Original publication

CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue. Ann Rheum Dis. Published 24 May 2025. doi:10.1016/j.ard.2025.04.018

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