RT Journal Article
SR Electronic
T1 Context-specific regulation of monocyte surface IL7R expression and soluble receptor secretion by a common autoimmune risk allele
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 262410
DO 10.1101/262410
A1 Hussein Al-Mossawi
A1 Nicole Yager
A1 Chelsea Taylor
A1 Evelyn Lau
A1 Sara Danielli
A1 Jelle de Wit
A1 James Gilchrist
A1 Isar Nassiri
A1 Elise A Mahe
A1 Wanseon Lee
A1 Laila Rizvi
A1 Seiko Makino
A1 Jane Cheeseman
A1 Matt Neville
A1 Julian C Knight
A1 Paul Bowness
A1 Benjamin P Fairfax
YR 2018
UL http://biorxiv.org/content/early/2018/07/15/262410.abstract
AB 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, yet a role for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level across multiple cell subsets and conditions in healthy individuals. We find monocyte surface and soluble IL7R (sIL7R) protein are markedly expressed in response to lipopolysaccharide (LPS). We further demonstrate alleles of rs6897932, a non-synonymous IL7R polymorphism associated with susceptibility to Multiple Sclerosis, Ankylosing Spondylitis and Primary Biliary Cirrhosis, form the key determinant of both surface IL7R and sIL7R in the context of inflammation. No effect of this allele was observed in unstimulated monocytes or across lymphoid subsets. Production of sIL7R by monocytes greatly exceeded that of CD4+ T-cells, and was strongly associated with both rs6897932 genotype and expression of the splicing factor gene DDX39A. Stimulated monocytes were sensitive to exogenous IL-7, which elicits a defined transcriptional signature. Flow cytometry and single-cell sequencing of synovial fluid derived monocytes from patients with spondyloarthritis showed an enlarged subset of IL7R+ monocytes with 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.