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

Cartography Consortium; Feng Liu; Hui Shi; Jason D. Turner; Rachel Anscombe; Jiaqi Li; Takuya Sekine; Ariane Hammitzsch; Devika Agarwal; Christopher Mahony; Jiewei Chen; Ben Kendrick; Dajiang Du; Qiang Tong; Lihua Duan; Kyla Dooley; Hai Fang; Ilya Korsunsky; Roopa Madhu; Adam P. Cribbs; Matthias Friedrich; Brian D. Marsden; Yi-Ling Chen; Graham Ogg; Anna Adams; Warner Chen; Steven Leonardo; Fiona E. McCann; Christopher D. Buckley; Terence Rooney; Thomas Freeman; Holm H. Uhlig; Calliope Dendrou; Adam Croft; Andrew Filer; Paul Bowness; Liye Chen

doi:10.1016/j.ard.2025.04.018

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

Cartography Consortium, Feng Liu, Hui Shi, Jason D. Turner, Rachel Anscombe, Jiaqi Li, Takuya Sekine, Ariane Hammitzsch, Devika Agarwal, Christopher Mahony, Jiewei Chen, Ben Kendrick, Dajiang Du, Qiang Tong, Lihua Duan, Kyla Dooley, Hai Fang, Ilya Korsunsky, Roopa Madhu, Adam P. CribbsMatthias Friedrich, Brian D. Marsden, Yi-Ling Chen, Graham Ogg, Anna Adams, Warner Chen, Steven Leonardo, Fiona E. McCann, Christopher D. Buckley, Terence Rooney, Thomas Freeman, Holm H. Uhlig, Calliope Dendrou, Adam Croft, Andrew Filer, Paul Bowness, Liye Chen^*

^*Corresponding author for this work

Inflammation and Ageing

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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.

Original language	English
Pages (from-to)	1151-1163
Number of pages	13
Journal	Annals of the Rheumatic Diseases
Volume	84
Issue number	7
Early online date	24 May 2025
DOIs	https://doi.org/10.1016/j.ard.2025.04.018
Publication status	Published - Jul 2025

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Cartography Consortium, Liu, F., Shi, H., Turner, J. D., 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., ... Chen, L. (2025). CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue. Annals of the Rheumatic Diseases, 84(7), 1151-1163. https://doi.org/10.1016/j.ard.2025.04.018

@article{6e1c08c9b7cb4a8c824dbfc38d5ef547,

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

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.",

author = "\{Cartography Consortium\} and Feng Liu and Hui Shi and Turner, \{Jason D.\} and Rachel Anscombe and Jiaqi Li and Takuya Sekine and Ariane Hammitzsch and Devika Agarwal and Christopher Mahony and Jiewei Chen and Ben Kendrick and Dajiang Du and Qiang Tong and Lihua Duan and Kyla Dooley and Hai Fang and Ilya Korsunsky and Roopa Madhu and Cribbs, \{Adam P.\} and Matthias Friedrich and Marsden, \{Brian D.\} and Yi-Ling Chen and Graham Ogg and Anna Adams and Warner Chen and Steven Leonardo and McCann, \{Fiona E.\} and Buckley, \{Christopher D.\} and Terence Rooney and Thomas Freeman and Uhlig, \{Holm H.\} and Calliope Dendrou and Adam Croft and Andrew Filer and Paul Bowness and Liye Chen",

year = "2025",

month = jul,

doi = "10.1016/j.ard.2025.04.018",

language = "English",

volume = "84",

pages = "1151--1163",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "7",

}

Cartography Consortium, 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, Friedrich, M, Marsden, BD, Chen, Y-L, 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 2025, 'CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue', Annals of the Rheumatic Diseases, vol. 84, no. 7, pp. 1151-1163. https://doi.org/10.1016/j.ard.2025.04.018

TY - JOUR

T1 - CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue

AU - Cartography Consortium

AU - Liu, Feng

AU - Shi, Hui

AU - Turner, Jason D.

AU - Anscombe, Rachel

AU - Li, Jiaqi

AU - Sekine, Takuya

AU - Hammitzsch, Ariane

AU - Agarwal, Devika

AU - Mahony, Christopher

AU - Chen, Jiewei

AU - Kendrick, Ben

AU - Du, Dajiang

AU - Tong, Qiang

AU - Duan, Lihua

AU - Dooley, Kyla

AU - Fang, Hai

AU - Korsunsky, Ilya

AU - Madhu, Roopa

AU - Cribbs, Adam P.

AU - Friedrich, Matthias

AU - Marsden, Brian D.

AU - Chen, Yi-Ling

AU - Ogg, Graham

AU - Adams, Anna

AU - Chen, Warner

AU - Leonardo, Steven

AU - McCann, Fiona E.

AU - Buckley, Christopher D.

AU - Rooney, Terence

AU - Freeman, Thomas

AU - Uhlig, Holm H.

AU - Dendrou, Calliope

AU - Croft, Adam

AU - Filer, Andrew

AU - Bowness, Paul

AU - Chen, Liye

PY - 2025/7

Y1 - 2025/7

N2 - 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.

AB - 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.

U2 - 10.1016/j.ard.2025.04.018

DO - 10.1016/j.ard.2025.04.018

M3 - Article

C2 - 40413112

SN - 0003-4967

VL - 84

SP - 1151

EP - 1163

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 7

ER -

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

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