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

Nature volume 410, pages 604–608 (2001)Cite this article

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.

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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.

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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.

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Author notes

  1. Jean-Claude D. Schwartz, Xuewu Zhang, Alexander A. Fedorov and Steven C. Almo: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Microbiology and Immunology,

    Jean-Claude D. Schwartz & Stanley G. Nathenson

  2. Department of Cell Biology,

    Xuewu Zhang & Stanley G. Nathenson

  3. Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    Alexander A. Fedorov & Steven C. Almo

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  1. Jean-Claude D. Schwartz
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Correspondence to Steven C. Almo.

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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

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