Structural Basis of the CD8αβ/MHC Class I Interaction: Focused Recognition Orients CD8β to a T Cell Proximal Position

Abstract

In the immune system, B cells, dendritic cells, NK cells, and T lymphocytes all respond to signals received via ligand binding to receptors and coreceptors. Although the specificity of T cell recognition is determined by the interaction of T cell receptors with MHC/peptide complexes, the development of T cells in the thymus and their sensitivity to Ag are also dependent on coreceptor molecules CD8 (for MHC class I (MHCI)) and CD4 (for MHCII). The CD8αβ heterodimer is a potent coreceptor for T cell activation, but efforts to understand its function fully have been hampered by ignorance of the structural details of its interactions with MHCI. In this study we describe the structure of CD8αβ in complex with the murine MHCI molecule H-2Dd at 2.6 Å resolution. The focus of the CD8αβ interaction is the acidic loop (residues 222–228) of the α3 domain of H-2Dd. The β subunit occupies a T cell membrane proximal position, defining the relative positions of the CD8α and CD8β subunits. Unlike the CD8αα homodimer, CD8αβ does not contact the MHCI α2- or β2-microglobulin domains. Movements of the CD8α CDR2 and CD8β CDR1 and CDR2 loops as well as the flexibility of the H-2Dd CD loop facilitate the monovalent interaction. The structure resolves inconclusive data on the topology of the CD8αβ/MHCI interaction, indicates that CD8β is crucial in orienting the CD8αβ heterodimer, provides a framework for understanding the mechanistic role of CD8αβ in lymphoid cell signaling, and offers a tangible context for design of structurally altered coreceptors for tumor and viral immunotherapy.