Structural Basis of the CD8alphabeta/MHC Class I Interaction: Focused Recognition Orients CD8beta to a T Cell Proximal Position

Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of Immunology (Impact Factor: 4.92). 09/2009; 183(4):2554-64. DOI: 10.4049/jimmunol.0901276
Source: PubMed


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 CD8alphabeta 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 CD8alphabeta in complex with the murine MHCI molecule H-2D(d) at 2.6 A resolution. The focus of the CD8alphabeta interaction is the acidic loop (residues 222-228) of the alpha3 domain of H-2D(d). The beta subunit occupies a T cell membrane proximal position, defining the relative positions of the CD8alpha and CD8beta subunits. Unlike the CD8alphaalpha homodimer, CD8alphabeta does not contact the MHCI alpha(2)- or beta(2)-microglobulin domains. Movements of the CD8alpha CDR2 and CD8beta 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 CD8alphabeta/MHCI interaction, indicates that CD8beta is crucial in orienting the CD8alphabeta heterodimer, provides a framework for understanding the mechanistic role of CD8alphabeta in lymphoid cell signaling, and offers a tangible context for design of structurally altered coreceptors for tumor and viral immunotherapy.

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    • "Until recently, the orientation of the CD8αβ heterodimer in complex with pMHCI was still speculated and the atomic structure of murine CD8αβ in complex with H-2D d , at 2.6 Ǻ resolution (Wang et al., 2009) revealed that the binding mode of the CD8αβ heterodimer was largely homologous to that of the CD8αα homodimer. Accordingly, the CDR-like loops of CD8αβ bound predominantly to the conserved finger-like loop in the H-2D d α3 domain. "
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    • "The triplets ITL (Ile-Thr-Leu) and DGR (Asp-Gly-Arg) are particularly interesting. For example, the triplet ITL is in the interface providing the binding between MHCI and CD8αβ (Wang et al. 2009). This triplet homology exists also in three GABAB1 receptor heteromers of human brain: GABAB1-GABAB2 forming the GABAB receptor (Marshall et al. 2001), GABAB1-mGluR1, and GABAB1-CXCR4 and may mediate the interaction in two of them (see Table 3 and Figure 1). "
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    • "Figure 4A is the overview of the structure of mouse CD8αβ heterodimer in complex with MHCI molecule H-2Dd (9). The overall structure is in a good agreement with previously published complex structures including the mouse CD8αα/H-2Kb (50) and human CD8αα/HLA-A2 (5) as well as mouse CD8αα homodimer in complex with non-classic MHCIb molecule TL (51). "
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