Abstract
IL-7 is a key factor in T-cell immunity and IL7R polymorphisms are implicated in autoimmune pathogenesis. We previously reported an expression quantitative trait locus (eQTL) at rs931555, 5’ to IL7R, associated with stimulated monocyte IL7R mRNA expression. Unlike in T-cells, a role for IL7R in monocyte biology is poorly described. Here we detail replication and characterization of this eQTL at the protein level across cell subsets and conditions in a separate cohort. We find rs6987932, a non-synonymous IL7R polymorphism associated Multiple Sclerosis, Ankylosing Spondylitis and Primary Biliary Cirrhosis susceptibility, is the key determinant of monocyte IL7R surface expression and soluble IL7R (sIL7R) release and functions in a context-specific manner. Monocyte surface IL7R is profoundly induced by LPS and TNF stimulation under genotypic regulation by rs6897932, whereas no geno-typic effect of this allele was observed in CD4+, CD8+ and CD56+ cells or un-stimulated monocytes. LPS-induced monocyte release of sIL7R was highly associated with both rs6897932 genotype and expression of the splicing factor gene DDX39A. After induction of IL7R expression human monocytes display a robust and pleiotropic transcriptional response to exogenous IL-7. Monocytes from the synovial fluid of patients with Spondyloarthritis expressed high levels of surface IL7R. These data demonstrate that disease-associated genetic variants in the IL7R gene critically impact monocyte IL7R and sIL7R expression following innate stimulation, suggesting a previously unappreciated key role for myeloid lineage cells in IL7 pathway biology in IL7R-associated diseases.