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

Jean-Claude D. Schwartz, Xuewu Zhang, Alexander A. Fedorov, Stanley G. Nathenson and Steven C. Almo ()
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Jean-Claude D. Schwartz: Department of Microbiology and Immunology
Xuewu Zhang: Department of Cell Biology
Alexander A. Fedorov: Albert Einstein College of Medicine
Stanley G. Nathenson: Department of Microbiology and Immunology
Steven C. Almo: Albert Einstein College of Medicine

Nature, 2001, vol. 410, issue 6828, 604-608

Abstract: 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.

Date: 2001
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DOI: 10.1038/35069112

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