Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS

Abstract

Optimal T cell activation requires the interactions of co-stimulatory molecules, such as those in the CD28 and B7 protein families. Recently, we described the co-stimulatory properties of the murine ligand to ICOS, which we designated as B7RP-1. Here, we report the co-stimulation of human T cells through the human B7RP-1 and ICOS interaction. This ligand-receptor pair interacts with a K:(D) approximately 33 nM and an off-rate with a t((1/2)) > 10 min. Interestingly, tumor necrosis factor (TNF)-alpha differentially regulates the expression of human B7RP-1 on B cells, monocytes and dendritic cells (DC). TNF-alpha enhances B7RP-1 expression on B cells and monocytes, while it inhibits it on DC. The human B7RP-1-Fc protein or cells that express membrane-bound B7RP-1 co-stimulate T cell proliferation in vitro. Specific cytokines, such as IFN-gamma and IL-10, are induced by B7RP-1 co-stimulation. Although IL-2 levels are not significantly increased, B7RP-1 co-stimulation is dependent on IL-2. These experiments define the human ortholog to murine B7RP-1 and characterize its interaction with human ICOS.

ICOS Costimulation Requires IL-2 and Can Be Prevented by CTLA-4 Engagement

“…A dose-dependent drop in cellular proliferation was observed in cultures treated with IL-2 Ab, whereas no effect was seen when a control Ab was added. Similar results were recently obtained by Yoshinaga and colleagues using a B7RP-1 fusion protein to stimulate T cells (27). These results indicate that ICOS-costimulated T cells produce small amounts of IL-2 that are immediately consumed by the T cells.…”

“…Although one group reported high levels of IL-2 production upon ICOS costimulation (20), most groups have reported undetectable levels of IL-2 in the supernatant (15,19,27). We also failed to detect IL-2 in the supernatant of ICOS-stimulated T cells (data not shown).…”

ICOS and B7 costimulatory molecule expression identifies activated cellular subsets in rheumatoid arthritis

“…T-cells become further activated via their constituitively expressed CD28 receptors when presented with antigen from an APC, along with appropriate signals from APC accessory molecules like B7.1 and B7.2. These interactions are known to provide potent proinflammatory signals to T-cells, resulting in autocrine IL-2 production, which is important for Tlymphocyte proliferation (1,3,5,(18)(19)(20)(21). Importance of CD28 costimulation has been directly demonstrated by blocking CD28 and B7 interactions and preventing T-cell responses in autoimmune disease models.…”

ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+T cells

“…Two splice variants of human ICOS-L have been described and designated hGL50 (3) and B7-H2͞B7RP-1͞hLICOS (4)(5)(6). Both molecules have an identical extracellular domain but differ at the carboxyl-terminal end of their cytoplasmic regions.…”