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

Regulation of T-cell activity is dependent on antigen-independent co-stimul atory 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 fo r T-cell. activation, whereas subsequent engagement of CTLA-4 with these I same ligands results in attenuation of the response(1). Given their central function in immune modulation, CTLA-4- and CD28- associated signalling pat hways are primary therapeutic targets for preventing autoimmune disease, gr aft versus host disease, graft rejection and promoting tumour immunity(1,2) . However, little is known about the cell-surface organization of these rec eptor/ ligand complexes and the structural basis for signal transduction, H ere we report the 3.2-Angstrom resolution structure of the complex between the disulphide-linked homodimer of human CTLA-4 and the receptor-binding do main 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 interf ace in each molecule and promote the formation of an alternating arrangemen t of bivalent CTLA-4 and B7-2 dimers that extends throughout the crystal. D irect observation of this CTLA-4/B7-2 network provides a model for the peri odic organization of these molecules within the immunological synapse and s uggests a distinct mechanism for signalling by dimeric cell-surface recepto rs.