Transcriptomic analysis of tissue resident memory T cell formation in arthritic synovium reveals multilineage progenitors with distinct differentiation programming 2813

Abstract Description Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint-specific memory. We identified CD8+ resident memory T cells (TRM) in human arthritic joints and demonstrated that TRM remain in the synovium during remission and mediate arthritis flares in murine models. To investigate the origin and differentiation of TRM in the joint, we used an antigen-induced murine arthritis model of flare and remission to evaluate the dynamic transcriptional changes of TRM formation. CD8 T cells were isolated from the synovium at several time points during the initiation and resolution of joint inflammation, and during arthritis remission. 10x single-cell RNA sequencing was performed, and trajectory analysis and cell ancestry of synovial TRM were computed. We identified that synovial TRM derived from both effector memory T cells (TEM) and central memory T cells (TCM) and verified their antigen-specificity through matched TCR sequencing. TCM-derived ancestors arose later in the arthritis course while TEM-derived ancestors appeared earlier in inflammation. We then confirmed the derivation of TRM from these progenitors in human synovial organoids. Further evaluation of gene expression dynamics during TRM differentiation reveal different timing of TRM-associated genes, potentially reflecting distinct roles of these genes in TRM formation. Targeting these TRM differentiation pathways could provide a novel therapeutic approach to joint-specific memory and chronic arthritis. Funding Sources NIH/NIAMS K08AR080992; Arthritis National Research Foundation; Rheumatology Research Foundation; Boston Children’s Hospital; Joint Biology Consortium; Arbuckle Family Research Fund Topic Categories Immune Mechanisms of Human Disease (HUM)