Title : Crystal
structure of the B7-1 /
CTLA-4 complex that inhibits human immune responses
Abstract :
- Optimal immune responses require both an antigen-specific and a co-stimulatory signal
- The shared ligands B7-1 and B7-2 on antigen-presenting cells deliver the co-stimulatory signal through CD28 and CTLA-4 on T cells
- Signalling through CD28 augments the T-cell response, whereas CTLA-4 signalling attenuates it
- Numerous animal studies and recent clinical trials indicate that manipulating these interactions holds considerable promise for immunotherapy
- With the consequences of these signals well established, and details of the downstream signalling events emerging, understanding the molecular nature of these extracellular interactions becomes crucial
- Here we report the crystal structure of the human CTLA-4 / B7-1 co-stimulatory complex at 3 .0 A resolution
- In contrast to other interacting cell-surface molecules, the relatively small CTLA-4 / B7-1 binding interface exhibits an unusually high degree of shape complementarity
- CTLA-4 forms homodimers 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 zipper-like oligomerization provides the structural basis for forming unusually stable signalling complexes at the T-cell surface, underscoring the importance of potent inhibitory signalling in human immune responses