Crystal structure of a soluble CD28-Fab complex

Naive T cell activation requires signaling by the T cell receptor and by nonclonotypic cell surface receptors. The mostimportant costimulatory protein is the monovalent homodimer CD28, which interacts with CD80 and CD86 expressed onantigen-presenting cells. Here we present the crystal structure of a soluble form of CD28 in complex with the Fab fragmentof a mitogenic antibody. Structural comparisons redefine the evolutionary relationships of CD28-related proteins, antigenreceptors and adhesion molecules and account for the distinct ligand-binding and stoichiometric properties of CD28 and therelated, inhibitory homodimer CTLA-4. Cryo-electron microscopy–based comparisons of complexes of CD28 with mitogenicand nonmitogenic antibodies place new constraints on models of antibody-induced receptor triggering. This work completesthe initial structural characterization of the CD28–CTLA-4–CD80–CD86 signaling system.Nonclonotypic costimulatory proteins expressed on the surfaces ofleukocytes profoundly influence the course of immune responses.CD28, the first of these molecules to be discovered, was initiallythought to satisfy the predictions of a ‘two-signal’ model of lympho-cyte activation