CD4+ tissue resident memory Th17 cells drive IL-17A-mediated joint pathology in Spondyloarthritis

  1. Feng Liu
  2. Hui Shi
  3. Jason D Turner
  4. Rachel Anscombe
  5. Takuya Sekine
  6. Ariane Hammitzsch
  7. Devika Agarwal
  8. Christopher Mahony
  9. Jiewei Chen
  10. Ben Kendrick
  11. Dajiang Du
  12. Qiang Tong
  13. Lihua Duan
  14. Kyla Dooley
  15. Hai Fang
  16. Ilya Korsunsky
  17. Roopa Madhu
  18. Adam P Cribbs
  19. Cartography consortium
  20. Matthias Friedrich
  21. Brian D. Marsden
  22. Yi-Ling Chen
  23. Graham Ogg
  24. Anna Adams
  25. Warner Chen
  26. Steven Leonardo
  27. Fiona E. McCann
  28. Christopher Buckley
  29. Terence Rooney
  30. Thomas Freeman
  31. Holm H. Uhlig
  32. Calliope Dendrou
  33. Adam Croft
  34. Andrew Filer
  35. Paul Bowness
  36. Liye Chen
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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 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 and 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 IL17A expression in SpA synovium was restricted to CD4+CXCR6+ TRM17 cells. 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 exhibited an enhanced IL-17A response signature. TRM17-like cells generated in vitro phenocopied the TRM17 found in joint tissue and produced IL-17A in response to T cell receptor (TCR) stimulation but not cytokines. IL-23 enhanced TCR-mediated IL-17F and IFN-γ but not IL-17A production. Perturbation of BRD1 inhibited the generation of TRM17-like cells.

Conclusions

CD4+ TRM17 cells are the predominant source of IL-17A in SpA. The TCR stimulation is essential for the secretion of IL-17A by TRM17-like cells. The epigenetic regulator BRD1 contributes to the generation of TRM17. Depleting TRM17 cells in SpA is a therapeutic strategy with potential to induce long-term remission.

Key messages

  • What is already known on this topic

    Interleukin (IL)-17A plays a key role in the immunopathogenesis of Spondyloarthritis (SpA), but its cellular source in joint tissue has not been determined previously. The induction of CD4+ tissue resident memory Th17 (TRM17) cells following the clearance of pathogens has been described in skin, lung and kidney. Whether CD4+ TRM17 cells contribute to the pathology of SpA is not clear.

  • What this study adds

  • CD4+ TRM17 cells are present in SpA synovial tissue and are the predominant source of IL17A

  • CD4+ TRM17 cells in SpA joints express IL17A without any in vitro exogenous stimulation

  • T cell receptor (TCR) rather than cytokine stimulation is essential for IL-17A production by TRM17-like cells

  • The epigenetic regulator BRD1 contributes to the generation of TRM17-like cells.

  • How this study might affect research, practice or policy

    This study demonstrates for the first time that CD4+ TRM17 cells are the main source of IL-17A in SpA synovial tissue, making a strong argument that future research of IL-17A pathology in SpA joint should focus on CD4+ TRM17 cells rather than circulating Th17 cells, CD8+ T cells, innate-like lymphocytes or innate lymphoid cells. In addition, our data suggest that targeting TRM17 cells, the “factory” of IL-17A, has the potential to induce long-term remission, encouraging future efforts to develop new therapies to deplete TRM17 cells in SpA joints.

    • Article activity feed

    1. Version published to 10.1101/2024.10.11.617865v1 on bioRxiv