Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Structural basis for co-stimulation by the human CTLA-4/B7-2 complex

Abstract

Regulation of T-cell activity is dependent on antigen-independent co-stimulatory signals provided by the disulphide-linked homodimeric T-cell surface receptors, CD28 and CTLA-4 (ref. 1). Engagement of CD28 with B7-1 and B7-2 ligands on antigen-presenting cells (APCs) provides a stimulatory signal for T-cell activation, whereas subsequent engagement of CTLA-4 with these same ligands results in attenuation of the response1. Given their central function in immune modulation, CTLA-4- and CD28-associated signalling pathways are primary therapeutic targets for preventing autoimmune disease, graft versus host disease, graft rejection and promoting tumour immunity1,2. However, little is known about the cell-surface organization of these receptor/ligand complexes and the structural basis for signal transduction. Here we report the 3.2-Å resolution structure of the complex between the disulphide-linked homodimer of human CTLA-4 and the receptor-binding domain of human B7-2. The unusual dimerization properties of both CTLA-4 and B7-2 place their respective ligand-binding sites distal to the dimer interface in each molecule and promote the formation of an alternating arrangement of bivalent CTLA-4 and B7-2 dimers that extends throughout the crystal. Direct observation of this CTLA-4/B7-2 network provides a model for the periodic organization of these molecules within the immunological synapse and suggests a distinct mechanism for signalling by dimeric cell-surface receptors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The CTLA-4/B7-2-binding interface.
Figure 2: The disulphide-linked human CTLA-4 dimer.
Figure 3: The human B7-2 dimer.
Figure 4: Molecular associations seen in the crystalline CTLA-4/B7-2 complex.

Similar content being viewed by others

References

  1. Oosterwegel, M. A., Greenwald, R. J., Mandelbrot, D. A., Lorsbach, R. B. & Sharpe, A. H. CTLA-4 and T cell activation. Curr. Opin. Immunol. 11, 294–300 (1999).

    Article  CAS  Google Scholar 

  2. Najafian, N. & Sayegh, M. H. CTLA4-Ig: a novel immunosuppressive agent. Expert Opin. Investig. Drugs 9, 2147–2157 (2000).

    Article  CAS  Google Scholar 

  3. Garcia, K. C., Teyton, L. & Wilson, I. A. Structural basis of T cell recognition. Annu. Rev. Immunol. 17, 369–397 (1999).

    Article  CAS  Google Scholar 

  4. Mastellar, E. L., Chuang, E., Mullen, A. C., Reiner, S. L. & Thompson, C. B. Structural analysis of CTLA-4 function in vivo. J. Immunol. 164, 5319–5327 (2000).

    Article  Google Scholar 

  5. Bork, P., Holm, L. & Sander, C. The immunoglobulin fold. Structural classification, sequence patterns and common core. J. Mol. Biol. 242, 309–320 (1994).

    CAS  Google Scholar 

  6. Ostrov, D. A., Shi, W., Schwartz, J. -C. D., Almo, S. C. & Nathenson, S. G. Structure of murine CTLA-4 and its role in modulating T cell responsiveness. Science 290, 816–819 (2000).

    Article  ADS  CAS  Google Scholar 

  7. Metzler, W. J. et al. Solution structure of human CTLA-4 and delineation of a CD80/CD86 binding site conserved in CD28. Nature Struct. Biol. 4, 527–531 (1997).

    Article  CAS  Google Scholar 

  8. Ikemizu, S. et al. Structure and dimerization of a soluble form of B7-1. Immunity 12, 51–60 (2000).

    Article  CAS  Google Scholar 

  9. Wang, J. H. et al. Structure of a heterophilic adhesion complex between the human CD2 and CD58 (LFA-3) counterreceptors. Cell 97, 791–803 (1999).

    Article  CAS  Google Scholar 

  10. Shapiro, L. et al. Structural basis of cell–cell adhesion by cadherins. Nature 374, 327–337 (1995).

    Article  ADS  CAS  Google Scholar 

  11. Morton, P. A. et al. Differential effects of CTLA-4 substitutions on the binding of human CD80 (B7-1) and CD86 (B7-2). J. Immunol. 156, 1047–1054 (1996).

    CAS  PubMed  Google Scholar 

  12. Peach, R. J. et al. Both extracellular immunoglobulin-like domains of CD80 contain residues critical for binding T cell surface receptors CTLA-4 and CD28. J. Biol. Chem. 270, 21181–21187 (1995).

    Article  CAS  Google Scholar 

  13. Peach, R. J. et al. Complementarity determining region 1 (CDR1)- and CDR3 analogous regions in CTLA-4 and CD28 determine the binding to B7-1. J. Exp. Med. 180, 2049–2058 (1994).

    Article  CAS  Google Scholar 

  14. Kariv, I., Truneh, A. & Sweet, R. W. Analysis of the site of interaction of CD28 with its counter-receptors CD80 and CD86 and correlation with function. J. Immunol. 157, 29–38 (1996).

    CAS  PubMed  Google Scholar 

  15. Truneh, A. et al. Differential recognition by CD28 of its cognate counter receptors CD80 (B7.1) and B70 (B7.2): analysis by site directed mutagenesis. Mol. Immunol. 33, 321–334 (1996).

    Article  CAS  Google Scholar 

  16. Leahy, D. J., Axel, R. & Hendrickson, W. A. Crystal structure of a soluble form of the human T cell coreceptor CD8 at 2.6 resolution. Cell 68, 1145–1162 (1992).

    Article  CAS  Google Scholar 

  17. Garcia, K. C. et al. An alphabeta T cell receptor structure at 2.5 A and its orientation in the TCR-MHC complex. Science 274, 209–219 (1996).

    Article  ADS  CAS  Google Scholar 

  18. Kwong, P. D. et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, 648–659 (1998).

    Article  ADS  CAS  Google Scholar 

  19. Lindsten, T. et al. Characterization of CTLA-4 structure and expression on human T cells. J. Immunol. 151, 3489–3499 (1993).

    CAS  Google Scholar 

  20. Anton van der Merwe, P., Davis, S. J. & Dustin, M. L. Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition. Semin. Immunol. 12, 5–21 (2000).

    Article  CAS  Google Scholar 

  21. Cunningham, B. C. et al. Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science 254, 821–825 (1991).

    Article  ADS  CAS  Google Scholar 

  22. Plotnikov, A. N., Schlessinger, J., Hubbard, S. R. & Mohammadi, M. Structural basis for FGF receptor dimerization and activation. Cell 98, 641–650 (1999).

    Article  CAS  Google Scholar 

  23. Wilson, I. A. & Jolliffe, L. K. The structure, organization, activation and plasticity of the erythropoietin receptor. Curr. Opin. Struct. Biol. 9, 696–704 (1999).

    Article  CAS  Google Scholar 

  24. Luo, R. Z. -T., Beniac, D. R., Fernandes, A., Yip, C. C. & Ottensmeyer, F. P. Quaternary structure of the insulin-insulin receptor complex. Science 285, 1077–1080 (1999).

    Article  CAS  Google Scholar 

  25. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 176, 307–326 (1997).

    Article  Google Scholar 

  26. Brunger, A. T. et al. Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta. Crystallogr. D 54, 905–921 (1998).

    Article  CAS  Google Scholar 

  27. Jones, T. A., Cowan, S., Zou, J. Y. & Kjeldgaard, M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991).

    Article  Google Scholar 

  28. Laskowski, R. A., MacArthur, M. W. & Thornton, J. M. Validation of protein models derived from experiment. Curr. Opin. Struct. Biol. 8, 631–639 (1998).

    Article  CAS  Google Scholar 

  29. Lawrence, M. C. & Colman, P. M. Shape complementarity at protein/protein interfaces. J. Mol. Biol. 234, 946–950 (1993).

    Article  CAS  Google Scholar 

  30. Evans, S. V. SETOR: hardware-lighted three-dimensional solid model representations of macromolecules. J. Mol. Graph. 11, 134–138 (1993).

    Article  CAS  Google Scholar 

  31. Barton, G. J. Protein multiple sequence alignment and flexible pattern matching. Methods Enzymol. 183, 403–428 (1990).

    Article  CAS  Google Scholar 

  32. Holm, L. & Sander, C. Dali: a network tool for protein structure comparison. Trends Biochem. Sci. 20, 478–480 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Scharff, P. Scherer, A. Davidson, A. Bresnick, T. DiLorenzo, A. Kalergis and M. Roden for comments. We also thank K. Rajashankar for assistance with data collection. This work was supported by grants from the National Institute of Allergies and Infectious Diseases. We acknowledge the support of the Albert Einstein Comprehensive Cancer Center.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Steven C. Almo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schwartz, JC., Zhang, X., Fedorov, A. et al. Structural basis for co-stimulation by the human CTLA-4/B7-2 complex. Nature 410, 604–608 (2001). https://doi.org/10.1038/35069112

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35069112

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing