The B7-CD28 paradigm revisited--- a systemic receptor array approach (178.19)

Abstract

Abstract T cell cosignaling pathways regulate T cell activation and control the fate of T cell responses. They consist of complex receptor-ligand interactions on cell surface between T cell and antigen presenting cell. The effort to identify co-signaling interactions has been hampered by low expression levels and weak affinities. We generated a comprehensive receptor array system in which over 2,500 human transmembrane proteins of hematopoietic system are expressed individually at high level and could be screened in a high throughput format to determine the binding partner of a fluorescence-labeled target protein. We report here the identification and characterization of two new interactions in the B7-CD28 family. Firstly, B7-H2, formerly known as the ligand for ICOS, is identified as the third ligand for CD28 and CTLA-4 in human. B7-H2 interacts with CD28 through a non-overlapping domain as B7-1 and B7-2. B7-H2-CD28 interaction is essential for the costimulation of human T cells’ primary responses to allogeneic antigens and memory recall responses. B7-H2-CD28 costimulation upregulates survival factor Bcl-xL, suppresses cell cycle inhibitor p27kip1 and induces signaling cascade of ERK and AKT kinases-dependent pathways. Secondly, B7-1 is identified as an inhibitory counter-receptor on T cell for B7-H1. Our study reveals new cosignaling interactions as potential targets for immune-modulation and provides a platform to rapidly discover receptor-ligand interactions in a large scale.