Background/Purpose: Rheumatoid arthritis (RA) 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 CD8 synovial resident memory T (TRM) cells persist in arthritic joints and mediate joint-specific memory. There is increasing recognition of diversity among TRM cells with distinct functional subsets described across tissues and diseases. Here, we evaluated the heterogeneity of CD8 TRM cells within arthritic synovium in humans and mice and investigated their developmental precursors.

Methods: We evaluated the gene expression profiles of memory T cells isolated from human RA synovium through 10x single-cell RNA sequencing. As we previously demonstrated CD8 TRM cells to be important for joint specific memory, we further evaluated subclusters of CD8 memory T cells from the synovium using Seurat and weighted gene co-expression network analysis packages. Cell clusters were annotated by the presence of known marker genes and comparison to published TRM gene expression signatures. We further evaluated the gene expression profiles of CD8 T cells isolated from the synovium of a mouse model of arthritis of flare and remission. CD8 T cells were isolated from the synovium at several time points across the course of arthritis through acute joint inflammation and remission and sequenced by 10x single-cell RNA sequencing. Synovial TRM cells were identified through transcriptomic profiles and presence in synovium during remission. Subclusters of CD8 TRM cells were further refined, and trajectory of analysis and cell ancestry of these synovial CD8 TRM cell clusters were computed with the Waddington Optimal Transport and Pseudotime analysis packages. We further confirmed the developmental progenitors of these TRM cells using human synovial organoids.

Results: We identified diversity among CD8 memory T cells in human RA synovium, including several subclusters of cells exhibiting transcriptomic profiles consistent with TRM. Gene Ontology enrichment analysis of highly expressed genes among TRM subclusters reveals pathways in T cell differentiation, granzyme-mediated programmed cell death signaling, and negative regulation of T cell apoptosis, suggesting distinct functions in cytotoxicity and tissue-adaptive programming. We identified similar TRM subpopulations in the synovium of murine arthritis during remission. Trajectory analysis revealed different timing in the emergence of these TRM subpopulations during arthritis, further implicating distinct roles in disease.

Conclusion: Our findings reveal heterogeneity within CD8 TRM cells in both murine and human synovial tissue. This diversity in function and timing of these TRM subpopulations suggests different roles in arthritis pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/single-cell-analysis-reveals-tissue-resident-memory-t-cells-heterogeneity-in-the-joint/