ADAM10 is a novel sheddase of Inducible Costimulatory Ligand (ICOSL).

Abstract

Abstract ICOSL is an important co-stimulatory molecule involved in the development of TH2 responses through germinal center reactions. Although not well defined, the regulation of ICOSL is known to occur through its interaction with ICOS. Evidence suggests surface expression levels are regulated by a catabolic event, and not through internalization. Here we confirm that regulation of ICOSL is mediated by the metalloproteinase ADAM10. Cleavage of recombinant ICOSL results in an amino-terminal fragment of approximately 3kDa, which is blocked by an ADAM10-specific inhibitor. Recombinant and cell-based cleavage assays suggest that ADAM17 can also cleave ICOSL. In vivo, we observed a ten-fold increase in ICOSL expression in ADAM10B−/− mice compared to wildtype, a phenomenon that was absent in ADAM17B−/− mice. This suggests that ADAM10 is the primary physiological sheddase of ICOSL, while ADAM17 may serve as a secondary sheddase. Additionally, ADAM10B−/− mice develop a significantly diminished T follicular helper (TFH) cell population in response to NP-KLH/alum immunization. Together, these data provide insight into the regulatory mechanism between ICOS/ICOSL and suggest ADAM10 may be a potential therapeutic target for attenuating antibody driven diseases.