Characterization of human inducible costimulator ligand expression and function

The inducible costimulator (ICOS) is the newest member of the CD28/CD152 re ceptor family involved in regulating T cell activation. We constructed a so luble-Ig fusion protein of the extracellular domain of human ICOS and used it as a Probe to characterize expression patterns of the ICOS ligand (ICOSL ). ICOSIg did not bind to CD80- or CD86-transfected Chinese hamster ovary c ell lines, demonstrating that ICOSL is distinct from those ligands identifi ed for CD28/CD152, ICOSIg showed selective binding to monocytic and B cell lines, whereas binding was undetectable on unstimulated monocytes and perip heral blood T and B cells. Expression of ICOSL was induced on monocytes aft er integrin-dependent plastic adhesion. Pretreatment of monocytes,vith mAb to the beta(2)-integrin subunit CD18 decreased adhesion and abolished ICOSL up-regulation but had no effect on CD80/86 (CD152 ligand (CD152L)) express ion. Both ICOSL and CD152L were up-regulated on monocytes by IFN-gamma but by distinct signaling pathways. Unlike CD152L expression, ICOSL expression did not change,when monocytes were differentiated into dendritic cells (DCs ) or after DCs were induced to mature by LPS, TNF-alpha, or CD40 ligation. Addition of ICOSIg to allogeneic MLRs between DCs and T cells reduced T cel l proliferative responses but did so less efficiently than CTLA4Ig (CD152Ig ) did. Similarly, ICOSIg also blocked Ag-specific T cell proliferation to t etanus toroid. Thus, ICOSL, like CD80/86, is expressed on activated monocyt es and dendritic cells but is regulated differently and delivers distinct s ignals to T cells that can be specifically inhibited by ICOSIg.