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: 5.36). 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.

Download full-text


Available from: David H Margulies, Aug 15, 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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. DOI:10.1007/s00251-012-0667-4 · 2.49 Impact Factor
  • Source
    • "This system helps to protect the host from infections and represented mainly by helper T (Th) and cytotoxic T (Tc) lymphocytes defined by the expression of specific markers CD4 and CD8 respectively. MHC molecules interact with either CD4/TCR/CD3 or CD8/TCR/CD3 complex on antigen presenting cells where CD3 serves as important trigger of T cell activation (Wang et al., 2009; Sun et al., 1995; Salter et al., 1989). TNF␣ as part of innate immune response reacts rapidly to different forms of stimuli such as bacteria, virus, parasitic infections, trauma, and ischemia/reperfusion (I/R) (reviewed in Kleinbongard et al. (2011)). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The heart is considered the powerhouse of the cardiovascular system. Heart and skeletal muscle inflammation (HSMI), cardiomyopathy syndrome (CMS) and pancreas disease (PD) are cardiac diseases of marine farmed Atlantic salmon (Salmo salar) which commonly affect the heart in addition to the skeletal muscle, liver and pancreas. The main findings of these diseases are necrosis and inflammatory cells infiltrates affecting different regions of the heart. In order to better characterize the cardiac pathology, study of the inflammatory cell characteristics and cell cycle protein expression was undertaken by immunohistochemistry. Immunohistochemistry was performed on paraffin embedded hearts from confirmed diseased cases applying specific antibodies. The inflammatory cells were predominantly CD3(+) T lymphocytes. The PD diseased hearts exhibited moderate hypoxia inducible factor-1α (HIF1α) immuno-reaction that suggested tissue hypoxia while recombinant tumor necrosis factor-α (rTNFα) antibody identified putative macrophages and eosinophilic granulocytes (EGCs) in addition to endocardial cells around lesions. There were strong to low levels of major histocompatibility complex (MHC) class II immunostaining in the diseased hearts associated with macrophage-like and lymphocyte-like cells. The diseased hearts expressed strong to low levels of apoptotic cells identified by caspase 3 and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) staining. The strong signals for proliferative cell nuclear antigen (PCNA) and TUNEL, and moderate levels of caspase 3 immuno-reactivity suggested a high cell turnover where DNA damage/repair might be occurring in the diseased hearts. Interestingly, the apparently similar cardiac diseases exhibited differences in the immunopathological responses in Atlantic salmon.
    Veterinary Immunology and Immunopathology 11/2012; 151(1-2). DOI:10.1016/j.vetimm.2012.10.004 · 1.75 Impact Factor
  • Source
    • "CD8b is reported to mediate interactions between the CD8 and the TCR– CD3 complex (Doucey et al, 2003). Because the affinities of the two isoforms for MHC-I molecules are similar (Garcia et al, 1996; Kern et al, 1999; Wang et al, 2009), and because Lck interacts with the cytoplasmic domain of CD8a, the likely mechanism for this difference in activity is the location of CD8ab in membrane rafts. The CD8b molecule, similar to the other T-cell co-receptor CD4, but unlike CD8a, can be palmitoylated, resulting in its localization in lipid rafts (Arcaro et al, 2000, 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bimolecular fluorescence complementation was used to engineer CD8 molecules so that CD8αα and CD8αβ dimers can be independently visualized on the surface of a T cell during antigen recognition. Using this approach, we show that CD8αα is recruited to the immunological synapse almost as well as CD8αβ, but because the kinase Lck associates preferentially with CD8αβ in lipid rafts, CD8αα is the weaker co-receptor. During recognition of the strong CD8αα ligand H2-TL, CD8αα is preferentially recruited. Thus, recruitment of the two CD8 species correlates with their relative binding to the available ligands, rather than with the co-receptor functions of the CD8 species.
    EMBO Reports 11/2011; 12(12):1251-6. DOI:10.1038/embor.2011.209 · 7.86 Impact Factor
Show more