Structural Basis for Clonal Diversity of the Public T Cell Response to a Dominant Human Cytomegalovirus Epitope

Gao, Mingming; Chen, Guobing; Pierce, Brian G.; Lu, Jinghua; Weng, Nan‐ping; Mariuzza, Roy A.

doi:10.1074/jbc.m115.691311

Cited by 37 publications

(55 citation statements)

References 58 publications

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“…In one study, SIV viral load was inversely correlated not with epitope-specific CD8 T cell frequency, recruitment to target organ, multifunctionality, or inability to recognize mutated virus, but rather with the number of public TCR clonotypes 23 , implying that the size of the TCR repertoire may be a critical component to understand efficient viral control. Despite the increasing availability of high-throughput TCR sequencing strategies 24 the breadth of TCR responding to human viral infection has been studied only in a few cases at sequence 25,26 or structural levels 27–29 and no study has been reported that combines both aspects.…”

mentioning

confidence: 99%

Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope

Song

Gil

Mishra

et al. 2017

Nat Struct Mol Biol

117

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A keystone of antiviral immunity is CD8 T-cell recognition of viral peptides bound to MHC-I proteins. The recognition mode of individual T cell receptors (TCRs) has been studied in some detail, but how TCR variation functions in providing a robust response to viral antigen is unclear. The influenza M1 epitope is an immunodominant target of CD8 T cells helping to control influenza in HLA-A2+ individuals. Here, we show that many distinct TCRs are used by CD8 T cells to recognize HLA-A2/M1, encoding different structural solutions to the problem of specifically recognizing a relatively featureless peptide antigen. The vast majority of responding TCRs target small clefts between peptide and MHC. These broad repertoires lead to plasticity in antigen recognition and protection against T cell clonal loss and viral escape.

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mentioning

confidence: 99%

Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope

Song

Gil

Mishra

et al. 2017

Nat Struct Mol Biol

117

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“…All other oligopeptides were derived from the IE-1 and pp65 proteins of human CMV (34). These oligopeptides were chosen because of both their known differences in eliciting a T cell response (34,35) and the reported crystal structures of 495 NLV in complex with HLA-A2 alone or with HLA-A2 and TCR (44)(45)(46).…”

Section: Computer Models Of 12 Oligopeptide × Hla Complexesmentioning

confidence: 99%

“…These interactions restrain the TCR interface with the peptide × HLA complex and provide a conserved structural scaffold for the TCR to "screen" the sequences of peptides presented by an HLA (7,50). The expansion is also necessary to accommodate the two canonical CDR3a/b loops (the last complementarity-determining region of the a-and b-chains) of the TCR and enable their interactions mainly with the central region of the peptide (44,46), which is required for the "pairing" of the TCR with its cognate Ag as shown in Fig. 2F (7, 50).…”

Section: Low Correlation Between Affinity and Immunogenicitymentioning

confidence: 99%

Peptide-Binding Groove Contraction Linked to the Lack of T Cell Response: Using Complex Structure and Energy To Identify Neoantigens

et al. 2018

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Using personalized peptide vaccines (PPVs) to target tumor-specific nonself-antigens (neoantigens) is a promising approach to cancer treatment. However, the development of PPVs is hindered by the challenge of identifying tumor-specific neoantigens, in part because current in silico methods for identifying such neoantigens have limited effectiveness. In this article, we report the results of molecular dynamics simulations of 12 oligopeptides bound with an HLA, revealing a previously unrecognized association between the inability of an oligopeptide to elicit a T cell response and the contraction of the peptide-binding groove upon binding of the oligopeptide to the HLA. Our conformational analysis showed that this association was due to incompatibility at the interface between the contracted groove and its αβ–T cell Ag receptor. This structural demonstration that having the capability to bind HLA does not guarantee immunogenicity prompted us to develop an atom-based method (SEFF12MC) to predict immunogenicity through using the structure and energy of a peptide·HLA complex to assess the propensity of the complex for further complexation with its TCR. In predicting the immunogenicities of the 12 oligopeptides, SEFF12MC achieved a 100% success rate, compared with success rates of 25–50% for 11 publicly available residue-based methods including NetMHC-4.0. Although further validation and refinements of SEFF12MC are required, our results suggest a need to develop in silico methods that assess peptide characteristics beyond their capability to form stable binary complexes with HLAs to help remove hurdles in using the patient tumor DNA information to develop PPVs for personalized cancer immunotherapy.

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“…The CDRs comprising the TCR chains are very effective at screening the various antigens presented to the T-cells. 9,17 It has been estimated by in vivo experiments that the TCR unique structures in humans are over >2.5x10 7 . 17,18 Despite the diverse numbers and the rigorous selection process of T-cells in the thymus, 19,20 there are cases where the selection process fails to single out T-cells reacting to self-antigens.…”

mentioning

confidence: 99%

“…9,17 It has been estimated by in vivo experiments that the TCR unique structures in humans are over >2.5x10 7 . 17,18 Despite the diverse numbers and the rigorous selection process of T-cells in the thymus, 19,20 there are cases where the selection process fails to single out T-cells reacting to self-antigens. 21 Thus, the failure in the thymic selection leads to self-reactive T-cells and induction of autoimmune disorders such as MS. 22,23 The myelin sheath consists of multiple proteins; MBP and PLP are two of the major component of the myelin sheath, while MOG and Myelin-associated Glycoprotein (MAG) are less abundant.…”

mentioning

confidence: 99%

Molecular dynamics at the receptor level of immunodominant myelin oligodendrocyte glycoprotein 35–55 epitope implicated in multiple sclerosis

Yannakakis

Tzoupis

Michailidou

et al. 2016

Journal of Molecular Graphics and Modelling

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Multiple Sclerosis (MS) is a common autoimmune disease whereby myelin is destroyed by the immune system. The disease is triggered by the stimulation of encephalitogenic T-cells via the formation of a trimolecular complex between the Human Leukocyte Antigen (HLA), an immunodominant epitope of myelin proteins and T-cell Receptor (TCR). Myelin Oligodendrocyte Glycoprotein (MOG) is located on the external surface of myelin and has been implicated in MS induction. The immunodominant 35-55 epitope of MOG is widely used for in vivo biological evaluation and immunological studies that are related with chronic Experimental Autoimmune Encephalomyelitis (EAE, animal model of MS), inflammatory diseases and MS. In this report, Molecular Dynamics (MD) simulations were used to explore the interactions of MOG35-55 at the receptor level. A detailed mapping of the developed interactions during the creation of the trimolecular complex is reported. This is the first attempt to gain an understanding of the molecular recognition of the MOG35-55 epitope by the HLA and TCR receptors. During the formation of the trimolecular complex, the residues Arg(41) and Arg(46) of MOG35-55 have been confirmed to serve as TCR anchors while Tyr(40) interacts with HLA. The present structural findings indicate that the Arg at positions 41 and 46 is a key residue for the stimulation of the encephalitogenic T-cells.

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Structural Basis for Clonal Diversity of the Public T Cell Response to a Dominant Human Cytomegalovirus Epitope

Cited by 37 publications

References 58 publications

Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope

Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope

Peptide-Binding Groove Contraction Linked to the Lack of T Cell Response: Using Complex Structure and Energy To Identify Neoantigens

Molecular dynamics at the receptor level of immunodominant myelin oligodendrocyte glycoprotein 35–55 epitope implicated in multiple sclerosis

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