Context-specific regulation of monocyte surface IL7R expression and soluble receptor secretion by a common autoimmune risk allele

IL-7 is a key factor in T-cell immunity and IL7R polymorphisms are implicated in autoimmune pathogenesis. IL7R mRNA is induced in stimulated monocytes in a genetically determined manner. Here we show monocyte surface and soluble IL7R (sIL7R) protein are markedly expressed in response to lipopolysaccharide (LPS). Flow cytometry of synovial fluid-derived monocytes from patients with spondyloarthritis showed an enlarged subset of IL7R+ monocytes. Single-cell RNA sequencing of ex-vivo derived monocytes from the synovial fluid and blood of patients revealed that IL7R+ monocytes at the inflammatory site have a unique transcriptional profile that markedly overlaps that induced by IL-7 in-vitro and shows similarity to the previously described 'Mono4' subset. These data demonstrate disease-associated genetic variants at IL7R specifically impact monocyte surface IL7R and sIL7R following innate immune stimulation, suggesting a previously unappreciated key role for monocytes in IL-7 pathway biology and IL7R-associated diseases.