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.

PD-1 and CTLA-4 Mediated Inhibitory Signaling for T cell Exhaustion during Chronic Viral Infections

“…Without CD28 ligation, TCR signals alone lead to T cell anergy. The topology of CTLA-4 homodimer allows for its bivalent binding to B7, while only monovalent binding occurs in CD28-B7 interaction [40]. Therefore, CTLA-4 binds these ligands with greater affinity and avidity compared to CD28, suggesting that CTLA-4 might block CD28 signaling by competitive binding to B7s.…”

The impact of protein characterization in structural proteomics

“…In the case of B7-1, the crystallographic dimer was shown to form in solution (Ikemizu et al, 2000). This permitted the development of models of interaction between B7-1 and CTLA-4 involving avidity enhancement of cell-cell interaction through the formation of extended zipperlike regions of attachment (Ikemizu et al, 2000;Stamper et al, 2001). AUC was used to show in addition that the homologous B7-2 is instead monomeric, thus being weakly stimulatory of a T-cell response whereas B7-1 is strongly inhibitory (Collins et al, 2002).…”

Evidence for CTLA4 as a susceptibility gene for dilated cardiomyopathy

“…Binding of CTLA4 to its B7 ligand interferes with the activation pathway and negatively affects the production of several cytokines, including interleukin-2, and the proliferation of T cells. 27,28 Activation of naive T cells requires two signals: (i) antigen recognition through T-cell receptor binding to the peptide-MHC complex and (ii) an antigen-independent pathway provided by interaction between CD28 expressed on the T-cell surface and B7. The CD28 homologue CTLA4 competes with the costimulatory CD28 receptor for binding to its ligands B7-1 (CD80) and B7-2 (CD86).…”