CD4+ tissue resident memory Th17 cells drive IL-17A-mediated joint pathology in Spondyloarthritis
Authors: Liu Feng , Shi Hui , Turner Jason D , Anscombe Rachel , Sekine Takuya , Hammitzsch Ariane , Agarwal Devika , Mahony Christopher , Chen Jiewei , Kendrick Ben , Du Dajiang , Tong Qiang , Duan Lihua , Dooley Kyla , Fang Hai , Korsunsky Ilya , Madhu Roopa , Cribbs Adam P ,   Cartography consortium, Friedrich Matthias , Marsden Brian D. , Chen Yi-Ling , Ogg Graham , Adams Anna , Chen Warner , Leonardo Steven , McCann Fiona E. , Buckley Christopher , Rooney Terence , Freeman Thomas , Uhlig Holm H. , Dendrou Calliope , Croft Adam , Filer Andrew , Bowness Paul , Chen Liye 
Published: October 2024

AbstractObjectivesInterleukin (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).MethodsSynovial 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 generatedin vitrousing 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.ResultsscRNA-seq showed thatIL17Aexpression in SpA synovium was restricted toCD4+CXCR6+TRM17 cells. Cell-cell communication and single-cell spatial analysis support the interaction between TRM17 andCLEC10A+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 generatedin vitrophenocopied 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.ConclusionsCD4+ 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 messagesWhat is already known on this topicInterleukin (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 addsCD4+ TRM17 cells are present in SpA synovial tissue and are the predominant source ofIL17ACD4+ TRM17 cells in SpA joints expressIL17Awithout anyin vitroexogenous stimulationT cell receptor (TCR) rather than cytokine stimulation is essential for IL-17A production by TRM17-like cellsThe epigenetic regulator BRD1 contributes to the generation of TRM17-like cells.How this study might affect research, practice or policyThis 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.