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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References
Schweitzer,A. N. & Sharpe,A. H. The complexity of the B7-CD28/CTLA-4 costimulatory pathway. Agents Actions 49, 33–43 (1998).
Lenschow,D. J., Walunas,T. L. & Bluestone,J. A. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 14, 233–258 (1996).
Chambers,C. A. & Allison,J. P. Co-stimulation in T cell responses. Curr. Opin. Immunol. 9, 396–404 (1997).
Hutloff,A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263–266 (1999).
Gross,J. A., St John,T. & Allison,J. P. The murine homologue of the T lymphocyte antigen CD28. Molecular cloning and cell surface expression. J. Immunol. 144, 3201–3210 (1990).
Brunet,J. F. et al. A new member of the immunoglobulin superfamily—CTLA-4. Nature 328, 267–270 (1987).
Bajorath,J. A molecular model of inducible costimulator protein and three-dimensional analysis of its reaction to the CD28 family of T cell-specific costimulatory receptors. J. Mol. Modeling 5, 169–176 (1999).
Linsley,P. S. et al. Binding stoichiometry of the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4). A disulfide-linked homodimer binds two CD86 molecules. J. Biol. Chem. 270, 15417–15424 (1995).
Aruffo,A. & Seed,B. Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. Proc. Natl Acad. Sci. USA 84, 8573–8577 (1987).
Freeman,G. J. et al. Murine B7-2, an alternative CTLA4 counter-receptor that costimulates T cell proliferation and interleukin 2 production. J. Exp. Med. 178, 2185–2192 (1993).
Greenfield,E. A., Nguyen,K. A. & Kuchroo,V. K. CD28/B7 costimulation: a review. Crit. Rev. Immunol. 18, 389–418 (1998).
Dutton,R. W., Bradley,L. M. & Swain,S. L. T cell memory. Annu. Rev. Immunol. 16, 201–223 (1998).
Beverley,P. C. Generation of T-cell memory. Curr. Opin. Immunol. 8, 327–330 (1996).
Inaba,K. et al. Identification of proliferating dendritic cell precursors in mouse blood. J. Exp. Med. 175, 1157–1167 (1992).
Simonet,W. S. et al. Long-term impaired neutrophil migration in mice overexpressing human interleukin-8. J. Clin. Invest. 94, 1310–1319 (1994).
Grabbe,S. & Schwarz,T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol. Today 19, 37–44 (1998).
Tang,A., Judge,T. A. & Turka,L. A. Blockade of CD40-CD40 ligand pathway induces tolerance in murine contact hypersensitivity. Eur. J. Immunol. 27, 3143–3150 (1997).
Tang,A., Judge,T. A., Nickoloff,B. J. & Turka,L. A. Suppression of murine allergic contact dermatitis by CTLA4Ig—tolerance induction of Th2 responses requires additional blockade of CD40-ligand. J. Immunol. 157, 117–125 (1996).
DeClerck,Y. A., Yean,T. D., Lu,H. S., Ting,J. & Langley,K. E. Inhibition of autoproteolytic activation of interstitial procollagenase by recombinant metalloproteinase inhibitor MI/TIMP-2. J. Biol. Chem. 266, 3893–3899 (1991).
Simonet,W. S. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997).
Brinster,R. L., Chen,H. Y., Trumbauer,M. E., Yagle,M. K. & Palmiter,R. D. Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc. Natl Acad. Sci. USA 82, 4438–4442 (1985).
McHale,J. F., Harari,O. A., Marshall,D. & Haskard,D. O. Vascular endothelial cell expression of ICAM-1 and VCAM-1 at the onset of eliciting contact hypersensitivity in mice: evidence for a dominant role of TNF-alpha. J. Immunol. 162, 1648–1655 (1999).
Wilcox,J. N. Fundamental principles of in situ hybridization. J. Histochem. Cytochem. 41, 1725–1733 (1993).
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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Yoshinaga, S., Whoriskey, J., Khare, S. et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402, 827–832 (1999). https://doi.org/10.1038/45582
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DOI: https://doi.org/10.1038/45582
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