T cell expression of inflammatory chemokine receptors

Brigham And Women'S Hospital, Boston MA

Investigators

Abstract

Abstract In chronic autoimmune conditions, lymphocytes are continuously recruited to the inflamed site to sustain the pathologic inflammatory response. T cells that migrate to inflamed tissues such as the synovium in rheumatoid arthritis often express chemokines receptors that detect chemokines produced in response to acute inflammatory mediators such as TNF or IL-1, including CLL2, CCL3, CCL4, CCL5, and CXCL16. Receptors for these chemokines, including CCR2, CCR5, and CXCR6, and highly enriched on T cells from joints of RA patients as compared to T cells in blood or secondary lymphoid organs. Despite the widespread expression of these receptors on T cells in inflamed sites, little is known about the extrinsic signals or transcription factors that induce their expression. Expression of CCR2, CCR5, and CXCR6 are not directly linked to a specific T cell effector subset, such as Th1 or Th17 cells; thus, we hypothesize that a distinct set of factors regulate expression of this migratory program independent of differentiated T cell effector subsets. Here we will use arrayed CRISPR screens and cytokine stimulation screens to identify transcription factors and cytokines that promote expression of CCR2, CCR5, CXCR6 and related chemokine receptors. We will use a combination of epigenetic analyses to identify common and distinct regulation patterns controlling the genes that encode these receptors. We will use spatial transcriptomics and human synovial organoids to dissect the interactions within RA synovium that may sustain expression of these receptors within an inflamed tissue. We expect that this project will reveal dominant pathways that control coordinated expression of receptors required for T cell migration to inflamed sites and will nominate new strategies to interfere with pathologic T cell migration therapeutically in ways that are more robust that targeting individual receptor-ligand interactions.