T Cell Receptors are Structures Capable of Initiating Signaling in the Absence of Large Conformational Rearrangements

Nuffield Department of Clinical Medicine and Medical Research Council Human Immunology Unit, The University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2012; 287(16):13324-35. DOI: 10.1074/jbc.M111.332783
Source: PubMed


Native and non-native ligands of the T cell receptor (TCR), including antibodies, have been proposed to induce signaling in T cells via intra- or intersubunit conformational rearrangements within the extracellular regions of TCR complexes. We have investigated whether any signatures can be found for such postulated structural changes during TCR triggering induced by antibodies, using crystallographic and mutagenesis-based approaches. The crystal structure of murine CD3ε complexed with the mitogenic anti-CD3ε antibody 2C11 enabled the first direct structural comparisons of antibody-liganded and unliganded forms of CD3ε from a single species, which revealed that antibody binding does not induce any substantial rearrangements within CD3ε. Saturation mutagenesis of surface-exposed CD3ε residues, coupled with assays of antibody-induced signaling by the mutated complexes, suggests a new configuration for the complex within which CD3ε is highly exposed and reveals that no large new CD3ε interfaces are required to form during antibody-induced signaling. The TCR complex therefore appears to be a structure that is capable of initiating intracellular signaling in T cells without substantial structural rearrangements within or between the component subunits. Our findings raise the possibility that signaling by native ligands might also be initiated in the absence of large structural rearrangements in the receptor.

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Available from: Claire F Jessup, Oct 06, 2015
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    • "Two models of TCR ectodomain topology on the T cell membrane are currently under consideration (Fernandes et al., 2012; Kim et al., 2012; Kuhns and Davis, 2012). Potential for αβ heterodimeric oligomerization differs in these two views. "
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    ABSTRACT: Despite major advances in T cell receptor (TCR) biology and structure, how peptide-MHC complex (pMHC) ligands trigger αβ TCR activation remains unresolved. Two views exist. One model postulates that monomeric TCR-pMHC ligation events are sufficient while a second proposes that TCR-TCR dimerization in cis via Cα domain interaction plus pMHC binding is critical. We scrutinized 22 known TCR/pMHC complex crystal structures, and did not find any predicted molecular Cα-Cα contacts in these crystals that would allow for physiological TCR dimerization. Moreover, the presence of conserved glycan adducts on the outer face of the Cα domain preclude the hypothesized TCR dimerization through the Cα domain. Observed functional consequences of Cα mutations are likely indirect, with TCR microclusters at the immunological synapse driven by TCR transmembrane/cytoplasmic interactions via signaling molecules, scaffold proteins, and/or cytoskeletal elements.
    Frontiers in Immunology 01/2013; 4:16. DOI:10.3389/fimmu.2013.00016
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    • "Specifically, they showed that the two CD3ε domains are juxtaposed upon assembly of the TCR-CD3 complex because the CD3e-EPOR chimera drove BaF3 growth in a TCR dependent manner (Kuhns et al., 2010). The CD3δ- and CD3γ-EPOR chimeras did not drive BaF3 growth in a TCR dependent manner and therefore are unlikely to be positioned next to each other as has been recently proposed (Fernandes et al., 2012). The TCR-CD3 complex architecture that is most consistent with the sum of the existing experimental data is one in which CD3δε and CD3γε associate with the TCR in an open face orientation. "
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    ABSTRACT: "How does T cell receptor signaling begin?" Answering this question requires an understanding of how the parts of the molecular machinery that mediates this process fit and work together. Ultimately this molecular architecture must (i) trigger the relay of information from the TCR-pMHC interface to the signaling substrates of the CD3 molecules and (ii) bring the kinases that modify these substrates in close proximity to interact, initiate, and sustain signaling. In this contribution we will discuss advances of the last decade that have increased our understanding of the complex machinery and interactions that underlie this type of signaling.
    Frontiers in Immunology 06/2012; 3:159. DOI:10.3389/fimmu.2012.00159
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    ABSTRACT: Adaptive immunity depends on specific recognition by a T-cell receptor (TCR) of an antigenic peptide bound to a major histocompatibility complex (pMHC) molecule on an antigen-presenting cell (APC). In addition, T-cell activation generally requires binding of this same pMHC to a CD4 or CD8 coreceptor. Here, we report the structure of a complete TCR-pMHC-CD4 ternary complex involving a human autoimmune TCR, a myelin-derived self-peptide bound to HLA-DR4, and CD4. The complex resembles a pointed arch in which TCR and CD4 are each tilted ∼65° relative to the T-cell membrane. By precluding direct contacts between TCR and CD4, the structure explains how TCR and CD4 on the T cell can simultaneously, yet independently, engage the same pMHC on the APC. The structure, in conjunction with previous mutagenesis data, places TCR-associated CD3εγ and CD3εδ subunits, which transmit activation signals to the T cell, inside the TCR-pMHC-CD4 arch, facing CD4. By establishing anchor points for TCR and CD4 on the T-cell membrane, the complex provides a basis for understanding how the CD4 coreceptor focuses TCR on MHC to guide TCR docking on pMHC during thymic T-cell selection.
    Proceedings of the National Academy of Sciences 03/2012; 109(14):5405-10. DOI:10.1073/pnas.1118801109 · 9.67 Impact Factor
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