Structural Basis of CD8 Coreceptor Function Revealed by Crystallographic Analysis of a Murine CD8αα Ectodomain Fragment in Complex with H-2Kb

Kern, Petra; Teng, Maikun; Smolyar, Alex; Liu, Jin-huan; Liu, Ju; Hussey, Rebecca E.; Spoerl, R.; Chang, Huiyou; Reinherz, Ellis L.; Wang, Jia-Huai

doi:10.1016/s1074-7613(00)80635-4

Cited by 172 publications

(207 citation statements)

References 57 publications

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“…Both the CD8 ␣-and ␤-chains are composed of a single extracellular Ig superfamily (IgSF) 3 variable (V) domain, a membrane-proximal hinge (H) region, a transmembrane domain (TM), and a cytoplasmic tail (CY). Biochemical and structural studies have shown that the Ig V domain of CD8␣, in conjunction with that of CD8␤, interacts with MHC class I molecules, thereby allowing the CD8 molecule to function as a coreceptor of the T cell Ag receptor (2)(3)(4)(5)(6)(7).…”

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Genomic Organization of the Chicken CD8 Locus Reveals a Novel Family of Immunoreceptor Genes

Liaw

Chen

Huang

et al. 2007

The Journal of Immunology

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The genomic organization of the chicken CD8α gene was investigated to determine the basis of its polymorphism. Contiguous to the CD8α gene we identified multiple DNA blocks possessing sequences homologous to CD8α. Gene conversions and recombination over evolutionary time among CD8α and these CD8α homologous genes seem to account for the observed polymorphism. Furthermore, these CD8α-like DNAs encode a distinct multigene family of immunoreceptors that have a charged or polar residue in place of the interspecies-conserved CD8α transmembrane proline residue and a short cytoplasmic tail nonhomologous to CD8α. The identification of this novel multigene family with an organization reminiscent of human killer Ig-like receptors raises compelling questions on their evolutionary relationship among immunoreceptors.

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Genomic Organization of the Chicken CD8 Locus Reveals a Novel Family of Immunoreceptor Genes

Liaw

Chen

Huang

et al. 2007

The Journal of Immunology

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“…The molecular interactions between CD8aa and MHCI molecules have been revealed by X-ray crystallographic studies in complexes of mouse CD8aa and its ligands, K b and TL, and also in complexes of human CD8aa and its ligand, HLA-A2 [21][22][23]. In both mouse and human CD8aa/pMHCI complexes, two CD8a subunits bind asymmetrically to pMHCI [21,22].…”

Section: Introductionmentioning

confidence: 99%

“…In both mouse and human CD8aa/pMHCI complexes, two CD8a subunits bind asymmetrically to pMHCI [21,22]. One subunit is involved in the dominant interaction that contributes to more than 70% of the total interaction surface between CD8 and pMHCI, the other subunit interacts only with the MHCI a3 domain [21,22]. The molecular structures of mouse CD8aa-complexed with K b and mouse CD8ab are very similar [24], suggesting that the CD8a or CD8b subunit in the CD8ab/pMHCI complex may mediate a dominant interaction.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, CD8b À/À mice produce approximately 20-30% the number of CD8SP thymocytes as their WT littermates [8][9][10]. Importantly, this observation indicates that CD8aa cannot substitute for CD8ab in supporting full thymic differentiation and suggests a critical role for CD8ab in this process.The molecular interactions between CD8aa and MHCI molecules have been revealed by X-ray crystallographic studies in complexes of mouse CD8aa and its ligands, K b and TL, and also in complexes of human CD8aa and its ligand, HLA-A2 [21][22][23]. In both mouse and human CD8aa/pMHCI complexes, two CD8a subunits bind asymmetrically to pMHCI [21,22].…”

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An active CD8α/pMHCI interaction is required for CD8 single positive thymocyte differentiation

et al. 2010

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Recognition of viral antigenic peptides bound to major histocompatibility complex class I molecules (MHCI) by TCR is critical for initiating the responses of CD8 1 T cells that ultimately lead to elimination of virus-infected cells. This antigen recognition is enhanced by the CD8 coreceptor through its interaction with the peptide-MHCI complexes (pMHCI). Mouse CD8ab can form two different complexes with pMHCI via either the CD8a-or CD8b-dominated interaction. To understand the functional significance of these complexes in vivo, we generated Tg mice carrying a variant CD8ab (CD8a m3 b) capable of forming only the CD8b-dominated CD8ab/pMHCI complex. These mice show sub-optimal thymic differentiation with reduced populations of CD8 1 single-positive thymocytes. Tg CD8 1 T cells exhibit a compromised developmental capacity when competing with CD8 1 T cells from B6 mice in mixed bone marrow chimera experiments. However, once these CD8 1 T cells have emigrated to the peripheral lymphoid organs, they exhibit normal effector function against viral infection. Our observations indicate that, in addition to the CD8 activity conferred by CD8b-dominated CD8ab/pMHCI complexes, full thymocyte differentiation requires additional coreceptor activities conferred by CD8aa and/or CD8ab with CD8a-dominated CD8/pMHCI complexes.Key words: CD8/pMHCI interaction . Coreceptor functions . T-cell differentiation .Viral infection . Tg mice Supporting Information available online IntroductionThe recognition of peptide antigen loaded on the major histocompatibility complex I (pMHCI) displayed on APC by the TCR is greatly enhanced by the simultaneous engagement of pMHCI with CD8 proteins on class I restricted CD8 1 T lymphocytes [1][2][3]. Such enhancement of antigen recognition is critical not only for triggering the activation of CD8 1 T cells but also for the differentiation of CD8 1 T cells in thymus [4][5][6][7][8][9][10]. Development of CD8 1 T cells in thymus starts with the differentiation of CD4 À CD8 À double negative (DN) precursor T cells into CD4 1 CD8 1 double positive (DP) cells, then into CD4 1 CD8b lo transition cells, and finally maturation into CD8 1 single positive (SP) cells [11][12][13][14]. After emigration into periphery, these CD8 1 T cells, in response to viral infection, can be activated by viral antigens and expanded as effector cytotoxic T lymphocytes, 836which are capable of eliminating the virus-infected cells [15]. The roles played by the interactions between CD8 proteins and MHCI in thymic differentiation and effector functions are not all clear.CD8 proteins are encoded by two genes, CD8a and CD8b, and expressed on the cell surface as homodimeric CD8aa and heterodimeric CD8ab [16]. Although both CD8aa and CD8ab bind to the classic MHCI molecules and function as coreceptors to enhance recognition of peptide antigens by TCR, CD8ab is apparently more efficient than CD8aa [17][18][19]. Surface expression of CD8b requires its heterodimerization with CD8a [20] and, consequently, no cellsurface CD8b protein can be de...

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The CD8α β co-receptor on double-positive thymocytes binds with differing affinities to the products of distinct class I MHC loci

et al. 2001

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Structural Basis of CD8 Coreceptor Function Revealed by Crystallographic Analysis of a Murine CD8αα Ectodomain Fragment in Complex with H-2Kb

Cited by 172 publications

References 57 publications

Genomic Organization of the Chicken CD8 Locus Reveals a Novel Family of Immunoreceptor Genes

Genomic Organization of the Chicken CD8 Locus Reveals a Novel Family of Immunoreceptor Genes

An active CD8α/pMHCI interaction is required for CD8 single positive thymocyte differentiation

The CD8α β co-receptor on double-positive thymocytes binds with differing affinities to the products of distinct class I MHC loci

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