T-cell activation requires co-stimulation through receptors such as CD28 and antigen-specific signalling through the T-cell antigen receptor. Here we describe a new murine costimulatory receptor-ligand pair. The receptor, which is related to CD28 and is the homologue of the human protein ICOS, is expressed on activated T cells and resting memory T cells. The ligand, which has homology to B7 molecules and is called B7-related protein-1 (B7RP-1), is expressed on B cells and macrophages. ICOS and B7RP-I do not interact with proteins in the CD28-B7 pathway, and B7RP-1 co-stimulates T cells in vitro independently of CD28. Transgenic mice expressing a B7RP-1-Fc fusion protein show lymphoid hyperplasia in the spleen, lymph nodes and Peyer's patches. Presensitized mice treated with B7RP-1-Fc during antigen challenge show enhanced hypersensitivity. Therefore, B7RP-1 exhibits co-stimulatory activities in vitro and in vivo. ICOS and B7RP-1 define a new and distinct receptor-ligand pair that is structurally related to CD28-B7 and is involved in the adaptive immune response.

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.

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Several strategies were used to isolate organisms involved in the uptake and subsequent release of inorganic phosphate from waste water sludge. These included direct staining for polyphosphates (polyP), growing in 32P inorganic phosphate followed by autoradiography, resistance to dicyclohexyl carbodiimide (DCCD), an ATPase inhibitor, and isolation on the basis of the buoyant density of the cell. Among those microorganisms isolated, three were identified as Acinetobacter lwoffii, A. calcoaceticus and Pseudomqnas vesicularis. The Ps. vesicularis culture had 31% of phosphate as polyP. 31P NMR analysis of the whole cells revealed the presence of polyP when the cultures were grown aerobic-ally to the late stationary phase and its subsequent loss during anaerobic incubation. Loss of polyP was also associated with a decrease in buoyant density of the cell. In the presence of DCCD, there was a decrease in the polyP peak, but a substantial increase in the sugar phosphates which is consistent with a hypothesis that polyP is used as a reserve energy source, Ps. vesicularis cells showed a two-fold increase in the level of polyphosphatase during early stationary phase, but a thirty fold increase in polyphosphate kinase activity during late stationary phase. This increased enzyme activity is consistent with the increased polyP synthesis during late stationary phase.

We conclude that WT (FR70) and the IgG2a depleting variant of CD70-specific antibody reduce graft infiltrating CD4 and CD8 T cells, transiently reduce serum alloantibody levels, and extend graft survival. In contrast, the nondepleting IgG1 variant of this antibody showed lower efficacy. These data suggest that a depleting mechanism of action and not merely costimulation blockade plays a substantial role in the therapeutic effects of CD70-specific antibody.