Regulation of T cell migratory programs in autoimmune disease

Abstract

In many autoimmune diseases activated T cells infiltrate tissues and propagate inflammation and tissue destruction. T cell migration is often orchestrated by chemokine receptors. These surface receptors allow T cells to follow gradients of chemokines into tissues or to localize within a tissue. In rheumatoid arthritis (RA), an autoimmune disease characterized by inflammation and destruction of the synovial joint, assessment of chemokine receptors on T cells by our group and others has highlighted the high expression of CCR2, CCR5, and CXCR6 in synovial fluid. While there is growing evidence for the importance of these receptors in RA, there is little understanding of what regulates these receptors. To better understand these receptors, we characterized the expression pattern of chemokine receptors in blood, synovial fluid, and tonsil and assessed the transcriptomic signatures underlying these receptors though bulk RNA-seq. This analysis identified a peripheral migratory program of cells co-expressing CCR2, CCR5, and CXCR6 and a mutually exclusive central migratory program expressing CCR7 and CXCR5. To determine factors that drive these migratory programs over a dozen cytokines were screened, which identified IFNβ as a driver of the peripheral program and TGFβ as a driver of the central program. To identify transcriptional regulators of the migratory programs, we leveraged bulk RNA-seq and ATAC-seq. Over 40 candidate transcription factors were identified, which were then evaluated in an arrayed CRISPR screen. PRDM1 and a combination of RUNX1, RUNX2, and RUNX3 were identified as core regulators of the peripheral versus central migratory programs. These transcription factors were able to alter broad transcriptomic signatures and T cell migration. Finally, we began to develop novel organoid models for testing T cell migration into synovial tissue. This work has identified major regulators of migratory programs involved in T cell infiltration into the inflamed sites.