Structural Basis of the CD8αβ/MHC Class I Interaction: Focused Recognition Orients CD8β 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

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 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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Available from: David H Margulies, Sep 29, 2015
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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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    ABSTRACT: Based on our theory, main triplets of amino acid residues have been discovered in cell-adhesion receptors (integrins) of marine sponges, which participate as homologies in the interface between two major immune molecules, MHC class I (MHCI) and CD8αβ. They appear as homologies also in several human neural receptor heteromers and subunits. The obtained results probably mean that neural and immune receptors also utilize these structural integrin triplets to form heteromers and ion channels, which are required for a tuned and integrated intracellular and intercellular communication and a communication between cells and the extracellular matrix with an origin in sponges, the oldest multicellular animals.
    SpringerPlus 12/2013; 2(1):128. DOI:10.1186/2193-1801-2-128
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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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    ABSTRACT: Since the discovery of co-receptor dependent αβTCR recognition, considerable effort has been spent on elucidating the basis of CD4 and CD8 lineage commitment in the thymus. The latter is responsible for generating mature CD4 helper and CD8αβ cytotoxic T cell subsets. Although CD4(+) and CD8(+) T cell recognition of peptide antigens is known to be MHC class II- and MHC class I-restricted, respectively, the mechanism of single positive (SP) thymocyte lineage commitment from bipotential double-positive (DP) progenitors is not fully elucidated. Classical models to explain thymic CD4 vs. CD8 fate determination have included a stochastic selection model or instructional models. The latter are based either on strength of signal or duration of signal impacting fate. More recently, differential co-receptor gene imprinting has been shown to be involved in expression of transcription factors impacting cytotoxic T cell development. Here, we address commitment from a structural perspective, focusing on the nature of co-receptor binding to MHC molecules. By surveying 58 MHC class II and 224 MHC class I crystal structures in the Protein Data Bank, it becomes clear that CD4 cannot bind to MHC I molecules, nor can CD8αβ or CD8αα bind to MHC II molecules. Given that the co-receptor delivers Lck to phosphorylate exposed CD3 ITAMs within a peptide/MHC (pMHC)-ligated TCR complex to initiate cell signaling, this strict co-receptor recognition fosters MHC class-restricted SP thymocyte lineage commitment at the DP stage even though both co-receptors are expressed on a single cell. In short, the binding preference of an αβTCR for a peptide complexed with an MHC molecule dictates which co-receptor subsequently binds, thereby supporting development of that subset lineage. How function within the lineage is linked further to biopotential fate determination is discussed.
    Frontiers in Immunology 11/2013; 4:383. DOI:10.3389/fimmu.2013.00383
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    • "Notably, the interactions of β 2 m– Lys58 and CD8α are only detected in CD8αα complexes, but not in the only CD8αβ complex solved to date (Wang et al. 2009), because the chains of the CD8αβ heterodimer are positioned differently when compared to the CD8αα homodimer. "
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    ABSTRACT: In major histocompatibility complex (MHC) class I molecules, monomorphic β(2)-microglobulin (β(2)m) is non-covalently bound to a heavy chain (HC) exhibiting a variable degree of polymorphism. β(2)M can stabilize a wide variety of complexes ranging from classical peptide binding to nonclassical lipid presenting MHC class I molecules as well as to MHC class I-like molecules that do not bind small ligands. Here we aim to assess the dynamics of individual regions in free as well as complexed β(2)m and to understand the evolution of the interfaces between β(2)m and different HC. Using human β(2)m and the HLA-B*27:09 complex as a model system, a comparison of free and HC-bound β(2)m by nuclear magnetic resonance spectroscopy was initially carried out. Although some regions retain their flexibility also after complex formation, these studies reveal that most parts of β(2)m gain rigidity upon binding to the HC. Sequence analyses demonstrate that some of the residues exhibiting flexibility participate in evolutionarily conserved β(2)m-HC contacts which are detectable in diverse vertebrate species or characterize a particular group of MHC class I complexes such as peptide- or lipid-binding molecules. Therefore, the spectroscopic experiments and the interface analyses demonstrate that β(2)m fulfills its role of interacting with diverse MHC class I HC as well as effector cell receptors not only by engaging in conserved intermolecular contacts but also by falling back upon key interface residues that exhibit a high degree of flexibility.
    Immunogenetics 12/2012; 65(3). DOI:10.1007/s00251-012-0667-4 · 2.23 Impact Factor
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