Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses

Optimal immune responses require both an antigen-specific and a co-stimulat ory signal. The shared ligands B7-1 and B7-2 on antigen-presenting cells de liver the co-stimulatory signal through CD28 and CTLA-4 on T cells. Signall ing through CD28 augments the T-cell response, whereas CTLA-4 signalling at tenuates it. Numerous animal studies(1,2) and recent clinical trials(3,4) i ndicate that manipulating these interactions holds considerable promise for immunotherapy, With the consequences of these signals well established, an d details of the downstream signalling events emerging(5-7), understanding the molecular nature of these extracellular interactions becomes crucial. H ere we report the crystal structure of the human CTLA-4/B7-1 co-stimulatory complex at 3.0 Angstrom resolution. In contrast to other interacting cell- surface molecules, the relatively small CTLA-4/B7-1 binding interface exhib its an unusually high degree of shape complementarity. CTLA-4 forms homodim ers through a newly defined interface of highly conserved residues. In the crystal lattice, CTLA-4 and B7-1 pack in a strikingly periodic arrangement in which bivalent CTLA-4 homodimers bridge bivalent B7-1 homodimers. This z ipper-like oligomerization provides the structural basis for forming unusua lly stable signalling complexes at the T-cell surface, underscoring the imp ortance of potent inhibitory signalling in human immune responses.