The interaction properties of costimulatory molecules revisited
Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, Stuart DI, van der Merwe PA, Davis SJ. (2002), Immunity. 17, 201-10
Abstract
B7-1 and B7-2 are generally thought to have comparable structures and affinities for their receptors, CD28 and CTLA-4, each of which is assumed to be bivalent. We show instead (1) that B7-2 binds the two receptors more weakly than B7-1, (2) that, relative to its CTLA-4 binding affinity, B7-2 binds CD28 2- to 3-fold more effectively than B7-1, (3) that, unlike B7-1, B7-2 does not self-associate, and (4) that, in contrast to CTLA-4 homodimers, which are bivalent, CD28 homodimers are monovalent. Our results indicate that B7-1 markedly favors CTLA-4 over CD28 engagement, whereas B7-2 exhibits much less bias. We propose that the distinct structures and binding properties of B7-1 and B7-2 account for their overlapping but distinct effects on T cell responses.
Key figure: Summary of Organization and Binding Properties of Signaling Complexes Formed by CD28, CTLA-4, B7-1, B7-2, ICOS, and LICOS
(A) Proposed structural changes to B7 family (B7F) and CD28 family (CD28F) proteins in the course of their evolution. Gene duplication and sequence divergence yielded monomeric and homodimeric, low- and high-affinity forms of the B7 family. Similarly, gene duplication and structural rearrangements (see Figure 7) generated low-affinity monovalent and high-affinity bivalent members of the CD28 family. The proposed precursors (boxed) are based on the properties of the avian homologs of these proteins (i.e., chicken CD28 and chCD80L; D.W.B. and J. Young, unpublished data). (B) Quaternary structures and binding properties of the signaling complexes formed by human CD28, CTLA-4, B7-1, B7-2, ICOS, and LICOS. The averaged affinities and measured or calculated kinetic constants for each interaction are also shown. The high- and low-affinity values shown for CTLA-4 interactions are for the two sites revealed by equilibrium binding analysis; only kinetic data relevant to the high-affinity binding site are presented. Data for B7-1 and LICOS interactions are from van der Merwe et al. (1997) and Brodie et al. (2000). N.D., not determined.
