Dunlap Garrett, Wagner Aaron, Meednu Nida, Zhang Fan, Jonsson A Helena, Wei Kevin, Sakaue Saori, Nathan Aparna, Bykerk Vivian P, Donlin Laura T, Goodman Susan M, Firestein Gary S, Boyle David L, Holers V Michael, Moreland Larry W, Tabechian Darren, Pitzalis Costantino, Filer Andrew, Raychaudhuri Soumya, Brenner Michael B, McDavid Andrew, Rao Deepak A, Anolik Jennifer H
Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School; Boston, MA, USA.
Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry; Rochester, NY, USA.
bioRxiv. 2023 Mar 21:2023.03.18.533282. doi: 10.1101/2023.03.18.533282.
Rheumatoid arthritis (RA) is an autoimmune disease initiated by antigen-specific T cells and B cells, which promote synovial inflammation through a complex set of interactions with innate immune and stromal cells. To better understand the phenotypes and clonal relationships of synovial T and B cells, we performed single-cell RNA and repertoire sequencing on paired synovial tissue and peripheral blood samples from 12 donors with seropositive RA ranging from early to chronic disease. Paired transcriptomic-repertoire analyses highlighted 3 clonally distinct CD4 T cells populations that were enriched in RA synovium: T peripheral helper (Tph) and T follicular helper (Tfh) cells, CCL5+ T cells, and T regulatory cells (Tregs). Among these cells, Tph cells showed a unique transcriptomic signature of recent T cell receptor (TCR) activation, and clonally expanded Tph cells expressed an elevated transcriptomic effector signature compared to non-expanded Tph cells. CD8 T cells showed higher oligoclonality than CD4 T cells, and the largest CD8 T cell clones in synovium were highly enriched in + cells. TCR analyses revealed CD8 T cells with likely viral-reactive TCRs distributed across transcriptomic clusters and definitively identified MAIT cells in synovium, which showed transcriptomic features of TCR activation. Among B cells, non-naive B cells including age-associated B cells (ABC), activated B cells, and plasma cells, were enriched in synovium and had higher somatic hypermutation rates compared to blood B cells. Synovial B cells demonstrated substantial clonal expansion, with ABC, memory, and activated B cells clonally linked to synovial plasma cells. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate RA synovium.
类风湿性关节炎(RA)是一种由抗原特异性T细胞和B细胞引发的自身免疫性疾病,这些细胞通过与固有免疫细胞和基质细胞的一系列复杂相互作用促进滑膜炎症。为了更好地了解滑膜T细胞和B细胞的表型及克隆关系,我们对12名血清阳性RA患者(疾病从早期到慢性)的配对滑膜组织和外周血样本进行了单细胞RNA和免疫组库测序。配对的转录组-免疫组库分析突出了3个在RA滑膜中富集的克隆性不同的CD4 T细胞群体:外周辅助性T细胞(Tph)和滤泡辅助性T细胞(Tfh)、CCL5+ T细胞以及调节性T细胞(Tregs)。在这些细胞中,Tph细胞显示出近期T细胞受体(TCR)激活的独特转录组特征,与未扩增的Tph细胞相比,克隆扩增的Tph细胞表达的转录组效应特征升高。CD8 T细胞比CD4 T细胞表现出更高的寡克隆性,滑膜中最大的CD8 T细胞克隆在 + 细胞中高度富集。TCR分析揭示了可能具有病毒反应性TCR的CD8 T细胞分布在转录组簇中,并明确鉴定出滑膜中的黏膜相关恒定T细胞(MAIT细胞),其显示出TCR激活的转录组特征。在B细胞中,包括年龄相关B细胞(ABC)、活化B细胞和浆细胞在内的非幼稚B细胞在滑膜中富集,并且与血液B细胞相比具有更高的体细胞超突变率。滑膜B细胞表现出大量的克隆扩增,ABC、记忆性和活化B细胞与滑膜浆细胞存在克隆联系。总之,这些结果揭示了浸润RA滑膜的功能不同的淋巴细胞群体之间的克隆关系。