T-cell co-stimulation through B7RP-1 and ICOS

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Abstract

T-cell activation requires co-stimulation through receptors such as CD28 (refs 1,2,3) and antigen-specific signalling through the T-cell antigen receptor. Here we describe a new murine co-stimulatory receptor–ligand pair. The receptor, which is related to CD28 and is the homologue of the human protein ICOS4, 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-1 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.

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Figure 1: Amino-acid sequences of ICOS and B7RP-1.
Figure 2: ICOS and B7RP-1 gene expression.
Figure 3: Interaction of ICOS with B7RP-1.
Figure 4: T-cell proliferation and cytokine secretion by B7RP-1 using B7RP-1–Fc (filled squares) and B7.2–Fc (filled circles) proteins.
Figure 5: Mesenteric lymph nodes and Peyer's patches from B7RP-1–Fc transgenic mice and control littermates.
Figure 6: Contact hypersensitivity.

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Acknowledgements

We thank the contributors to the Amgen Genome Program, in particular, F. J. Calzone, for direction and assistance during the course of this work. Special thanks to K. Christensen and C. DiPalma for assistance with the preparation and the analysis of the transgenic mice, and to B. Yoshinaga and E. Medlock for assistance with the preparation of this manuscript.

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Correspondence to Steven K. Yoshinaga.

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Yoshinaga, S., Whoriskey, J., Khare, S. et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402, 827–832 (1999) doi:10.1038/45582

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