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Author(s): Anna Tafuri [1, 2, 3]; Arda Shahinian [1, 2, 3]; Friedhelm Bladt [1, 4]; Steve K. Yoshinaga [5]; Manel Jordana [6]; Andrew Wakeham [2, 3]; Louis-Martin Boucher [2, 3]; [...]

It has been possible to establish the human protein ICOS and the ligand B7-related protein-1 (B7RP-1) as a receptor-ligand pair able to undertake extensive co-stimulatory activity in vitro and in vivo. This pair has structural links with CD28-B7 and participates in the adaptive immune response. It was found that the interaction between ICOS and B7RP-1 is specific and separate from that taking place between CD28 and B7.

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 KD ~ 33 nM and an off-rate with a t½ > 10 min. Interestingly, tumor necrosis factor (TNF)-α differentially regulates the expression of human B7RP-1 on B cells, monocytes and dendritic cells (DC). TNF-α 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-γ 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. [ABSTRACT FROM PUBLISHER]

The B7 costimulatory molecules govern many aspects of T cell immune responses by interacting with CD28 for costimulation, but also with CTLA-4 for immune suppression. Although blockade of CTLA-4 with Ab in humans undergoing cancer immune therapy has led to some cases of inflammatory bowel disease, spontaneous animal models of colitis that depend upon modulation of B7 interactions have not been previously described. In this study, we demonstrate that mice expressing a soluble B7-2 Ig Fc chimeric protein spontaneously develop colitis that is dependent on CD28-mediated costimulation of CD4(+) T cells. We show that the chimeric protein has mixed agonistic/antagonist properties, and that it acts in part by blocking the cell intrinsic effects on T cell activation of engagement of CTLA-4. Disease occurred in transgenic mice that lack expression of the endogenous B7 molecules (B7 double knock-out mice), because of the relatively weak costimulatory delivered by the chimeric protein. Surprisingly, colitis was more severe in this context, which was associated with the decreased number of Foxp3(+) regulatory T cells in transgenic B7 double knock-out mice. This model provides an important tool for examining how B7 molecules and their effects on CTLA-4 modulate T cell function and the development of inflammatory diseases.