Th114 - Signatures of T Cell Migratory Receptor Expression in Rheumatoid Arthritis Joints

Abstract Text: Rheumatoid arthritis (RA) is an autoimmune disease characterized by T cell infiltration into the synovium. T cell migration into inflamed sites is controlled in part by expression of chemokine receptors that enable migration towards chemokines produced at sites of inflammation. Here, we characterized the expression of chemokine receptors on T cells that accumulate in synovial fluid and tissue of RA patients. T cells in synovial fluid are markedly enriched for expression of CCR2, CCR5, and CXCR6, three receptors that detect ‘inflammatory’ chemokines, compared to blood T cells. These receptors are often co-expressed and expressed separately from CCR7 and CXCR5. We further investigated these migratory programs by generating bulk RNA-seq data on T cell populations from synovial fluid and blood sorted on chemokine receptor expression. CCR2/CCR5/CXCR6+ cells had distinct transcriptional signatures compared to CCR7/CXCR5+ cells. CCR2/CCR5/CXCR6+ T cells were enriched for transcriptomic signatures associated with T peripheral helper cells selectively in seropositive RA samples. We utilized these datasets and ATAC-seq data to identify candidate transcription factors (TFs) that may regulate chemokine receptor expression, focusing on TFs that were upregulated in CCR2/CCR5/CXCR6+ cells and had a likely binding site at a chemokine receptor locus. We tested these candidates in an arrayed CRISPR screen in human CD4 T cells and identified specific TFs that promoted or inhibited CCR2, CCR5, and CXCR6 expression on T cells. Here we have defined a migratory program of RA synovial T cells and identified candidate regulators that may influence T cell infiltration into inflamed synovium.