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

Interleukin (IL)-17A plays a central role in driving joint pathology in Spondyloarthritis (SpA). In this study, synovial tissues from patients with Axial SpA and Psoriatic arthritis were analyzed using single-cell RNA sequencing and spatial RNA profiling to pinpoint the cellular source of IL-17A. The results revealed that IL-17A expression is exclusively localized to CD4?CXCR6? tissue resident memory Th17 (TRM17) cells, which interact with activated CLEC10A? dendritic cells within the joint. These interactions coincide with an enhanced IL-17A response signature in both sublining and lining fibroblasts. Furthermore, in vitro-generated TRM17-like cells from blood memory CD4? T cells recapitulated the in situ characteristics by producing IL-17A in response to T cell receptor stimulation, while IL-23 selectively amplified TCR-mediated IL-17F and IFN-? production. Importantly, perturbation of the epigenetic regulator BRD1 impaired the generation of TRM17-like cells. These findings underscore the predominant role of TRM17 cells as the source of IL-17A in SpA and suggest that targeting BRD1 or depleting TRM17 cells may offer promising therapeutic strategies for achieving long-term disease remission. Overall design: Synovial tissues from patients with spondyloarthritis (SpA) were analyzed by single-cell RNA sequencing, including five axial SpA (AxSpA) and six psoriatic arthritis (PsA) samples. Due to national regulations governing genetic data, three of the five AxSpA datasets generated at Shanghai Sixth People's Hospital are not deposited in the GEO repository; these datasets are available upon request through a formal data access application.

白细胞介素(Interleukin, IL)-17A在脊柱关节炎(Spondyloarthritis, SpA)的关节病理发生过程中发挥核心驱动作用。本研究针对中轴型脊柱关节炎(Axial SpA)与银屑病关节炎(Psoriatic arthritis, PsA)患者的滑膜组织，采用单细胞RNA测序(single-cell RNA sequencing)与空间RNA谱分析(spatial RNA profiling)技术，精准定位IL-17A的细胞来源。结果显示，IL-17A的表达仅局限于CD4⁺CXCR6⁺组织驻留记忆性Th17细胞(tissue resident memory Th17, TRM17)，这类细胞可与关节内活化的CLEC10A⁺树突状细胞(CLEC10A⁺ dendritic cells)发生相互作用。上述相互作用同时伴随滑膜衬下层与衬里层成纤维细胞(fibroblasts)中IL-17A应答特征的增强。进一步研究发现，从外周血记忆性CD4⁺T细胞体外(in vitro)诱导获得的TRM17样细胞，可通过T细胞受体(T cell receptor, TCR)刺激产生IL-17A，从而重现体内原位的细胞特性；而IL-23可选择性增强TCR介导的IL-17F与干扰素γ(Interferon-γ, IFN-γ)的产生。值得注意的是，表观遗传调控因子(epigenetic regulator)BRD1的功能扰动会抑制TRM17样细胞的生成。本研究结果证实了TRM17细胞作为SpA中IL-17A主要来源的核心地位，并提示靶向BRD1或清除TRM17细胞或可成为实现长期疾病缓解的潜在治疗策略。

总体实验设计：本研究通过单细胞RNA测序分析脊柱关节炎(SpA)患者的滑膜组织，共纳入5例中轴型脊柱关节炎(AxSpA)样本与6例银屑病关节炎(PsA)样本。受限于遗传数据相关国家法规，在上海市第六人民医院生成的5份AxSpA数据集中有3份未上传至基因表达综合数据库(Gene Expression Omnibus, GEO)，此类数据集需通过正式的数据访问申请方可获取。