Background/Purpose: Rheumatoid arthritis is a chronic autoimmune disease characterized by joint-specific memory, the phenomenon in which arthritis repeatedly flares in the same joints. We previously demonstrated that joint-specific memory is mediated by CD8+ synovial resident memory T (T_RM) cells that persist in arthritic joints during remission and can mediate joint-specific flares. Depleting T_RM cells from the joint results in an attenuation of arthritis flares, suggesting that targeting T_RM cells could be a novel option to alleviate pathogenesis and disease chronicity. However, little is known about the origin and differentiation of T_RM cells in the joint. Here, we investigated the dynamic transcriptional changes of T_RM cell formation in the joint during inflammation and remission.

Methods: We used a murine arthritis model where OT-I T cells were adoptively transferred into recipient mice and arthritis was induced by intraarticular ovalbumin injection. CD8 T cells were isolated from the synovium at several time points—days 3, 4, 5, 6, 7, and 8 during initiation and resolution of acute joint inflammation, and days 18 and 28 during arthritis remission. Transcriptomic profiles of sorted CD8+ T cells were acquired by 10x single-cell RNA sequencing and analyzed using Seurat and weighted gene co-expression network analysis packages. Trajectory analysis and cell ancestry of synovial T_RM cells were computed with the Waddington Optimal Transport analysis package. We then evaluated the dynamic gene expression patterns in T_RM cell differentiation in human synovium organoids in which T_RM cells were derived from peripheral blood mononuclear cells.

Results: We identified a group of synovial CD8 T cells with a T_RM cell gene expression signature that was present in the synovium at Days 18 and 28 of arthritis remission. Trajectory analysis revealed that synovial T_RM cells derived from both central memory T cells and effector memory T cells, and we confirmed the antigen-specificity of both the progenitors and T_RM cells through matched TCR sequencing. We identified four distinct patterns of gene expression changes during T_RM cell formation—1) genes expressed during acute arthritis that are downregulated during remission; 2) genes that show low expression during acute arthritis and are upregulated during remission (i.e. Runx3); 3) genes that are gradually upregulated through the entire time course; 4) genes that highly upregulated during the later phases of acute inflammation and then show moderate expression during remission (i.e. Zfp683, Itga1, Il15ra).

Conclusion: Our studies suggest that synovial CD8 T_RM cells are derived from antigen-specific circulating effector cells. The various patterns of gene expression changes during T_RM cell development may reflect differing roles of these canonical T_RM cell genes in T_RM cell formation. Targeting these T_RM cell differentiation pathways could provide a novel therapeutic approach to joint-specific memory and chronic arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcriptional-changes-in-the-formation-of-tissue-resident-memory-t-cells-in-the-joint/