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

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 CD8 alpha beta 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 CD8 alpha beta in complex with the murine MHCI molecule H-2D(d) at 2.6 angstrom resolution. The focus of the CD8 alpha beta interaction is the acidic loop (residues 222-228) of the alpha 3 domain of H-2D(d). The beta subunit occupies a T cell membrane proximal position, defining the relative positions of the CD8 alpha and CD8 beta subunits. Unlike the CD8 alpha homodimer, CD8 alpha beta does not contact the MHCI alpha(2)- or beta(2)-microglobulin domains. Movements of the CD8 alpha CDR2 and CD8 beta CDR1 and CDR2 loops as well as the flexibility of the H-2D(d) CD loop facilitate the monovalent interaction. The structure resolves inconclusive data on the topology of the CD8 alpha beta/MHCI interaction, indicates that CD8 beta is crucial in orienting the CD8 alpha beta heterodimer, provides a framework for understanding the mechanistic role of CD8 alpha beta in lymphoid cell signaling, and offers a tangible context for design of structurally altered coreceptors for tumor and viral immunotherapy. The Journal of Immunology, 2009, 183: 2554-2564.