T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I–bound peptide

Tynan, Fleur Elizabeth; Burrows, Scott R.; Buckle, Ashley M.; Clements, Craig Steven; Borg, Natalie A.; Miles, John J.; Beddoe, Travis; Whisstock, James C.; Wilce, Matthew Charles James; Silins, Sharon L.; Burrows, Jacqueline M.; Kjer‐Nielsen, Lars; Kostenko, Lyudmila; Purcell, Anthony W.; McCluskey, James; Rossjohn, Jamie

doi:10.1038/ni1257

Cited by 259 publications

(292 citation statements)

References 65 publications

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“…Typically, these involve highly related allotypes that exhibit limited sequence differences, which nevertheless often result in biologically significant changes in conformation of the peptide and/or the MHC-I molecule (2,(61)(62)(63). In contrast, despite the comparatively low level of sequence identity between Qa-1 b and HLA-E, remarkably, they present their respective peptide cargoes in a very similar manner for recognition by CD94-NKG2 receptors.…”

Section: Discussionmentioning

confidence: 99%

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

Sullivan

Vivian

et al. 2012

The Journal of Immunology

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The primary function of the monomorphic MHC class Ib molecule Qa-1b is to present peptides derived from the leader sequences of other MHC class I molecules for recognition by the CD94-NKG2 receptors expressed by NK and T cells. Whereas the mode of peptide presentation by its ortholog HLA-E, and subsequent recognition by CD94-NKG2A, is known, the molecular basis of Qa-1b function is unclear. We have assessed the interaction between Qa-1b and CD94-NKG2A and shown that they interact with an affinity of 17 μM. Furthermore, we have determined the structure of Qa-1b bound to the leader sequence peptide, Qdm (AMAPRTLLL), to a resolution of 1.9 Å and compared it with that of HLA-E. The crystal structure provided a basis for understanding the restricted peptide repertoire of Qa-1b. Whereas the Qa-1b-AMAPRTLLL complex was similar to that of HLA-E, significant sequence and structural differences were observed between the respective Ag-binding clefts. However, the conformation of the Qdm peptide bound by Qa-1b was very similar to that of peptide bound to HLA-E. Although a number of conserved innate receptors can recognize heterologous ligands from other species, the structural differences between Qa-1b and HLA-E manifested in CD94-NKG2A ligand recognition being species specific despite similarities in peptide sequence and conformation. Collectively, our data illustrate the structural homology between Qa-1b and HLA-E and provide a structural basis for understanding peptide repertoire selection and the specificity of the interaction of Qa-1b with CD94-NKG2 receptors.

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Section: Discussionmentioning

confidence: 99%

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

Sullivan

Vivian

et al. 2012

The Journal of Immunology

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“…5C). These experiments revealed that the TCRs generated in these four donors were sensitive to amino acid substitution at positions 4,5,6,7,8,9, or 10 of the RPH peptide. These data illustrate the functional diversity generated within the RPHspecific TCR repertoire across the population as a result of the 21.5-kb deletion in the TCR b locus.…”

Section: Structure Of the Rph-hla-b*0702 Complexmentioning

confidence: 99%

“…Despite this vast potential repertoire, immune responses often show strong bias in TCR selection, resulting in immunodominance of certain "public" TCRs that are widely used in individuals with shared MHC types (2)(3)(4)(5). Structural studies have shown that biased TCR usage arises from unique specificity requirements for a given peptide-MHC complex (6,7). Furthermore, TCR production frequency during recombination in the thymus also contributes to bias in TCR usage in Ag-specific responses, with public TCRs generally produced with fewer random nucleotide additions in their sequence (8).…”

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confidence: 99%

The Impact of a Large and Frequent Deletion in the Human TCR β Locus on Antiviral Immunity

Brennan

Petersen

Neller

et al. 2012

The Journal of Immunology

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The TCR plays a critical role in recognizing intracellular pathogens and initiating pathways leading to the destruction of infected cells by the immune system. Although genetic variability is known to greatly impact on the human immune system and the outcome of infection, the influence of sequence variation leading to the inactivation or deletion of TCR gene segments is unknown. To investigate this issue, we examined the CD8+ T cell response to an HLA-B7–restricted epitope (265RPHERNGFTVL275) from the pp65 Ag of human CMV that was highly biased and frequently dominated by a public TCR β-chain encoded by the variable gene segment TRBV4-3. Approximately 40% of humans lack T cells expressing TRBV4-3 because of a 21.5-kb insertion/deletion polymorphism, but these individuals remain responsive to this epitope, using a diverse T cell repertoire characterized by private TCR usage. Although most residues within the bulged 11-mer peptide were accessible for TCR contact, the public and private TCRs showed distinct patterns of sensitivity to amino acid substitution at different positions within the peptide, thereby suggesting that the repertoire diversity generated in the absence of the dominant public TRBV4-3+ TCR could lead to better protection from viral escape mutation. Thus, variation in the size of the TRBV repertoire clearly contributes toward interindividual variability in immune responses and is presumably maintained in many ethnic groups to enhance the diversity of Ag-specific T cell responses.

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“…This analysis reveals that, for certain locations, particularly in loop regions such as residues 39-42 of the a1-domain and a conspicuous stretch of three residues (149-151) within the N-terminal region of the a2-helix, the positions of the Ca atoms in the two structures differ by more than 1.0 Å. Similar domain-wise analyses of other regions of the structure show Ca shifts larger than 0.5 Å at several positions in the a3 domain and at residues [46][47][48][49]59, and 96-99 in b 2 m. The comparison demonstrates also that the a3-domain has most main chain shifts (0.50-1.13 Å) and differences in side chain orientations, although nearly all residues having such differences are part of loop regions.…”

Section: Structural Features Of the Hla-a1:mage-a1 Complexmentioning

confidence: 82%

Conformational changes within the HLA‐A1:MAGE‐A1 complex induced by binding of a recombinant antibody fragment with TCR‐like specificity

et al. 2008

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Although there is X-ray crystallographic evidence that the interaction between major histocompatibility complex (MHC, in humans HLA) class I molecules and T cell receptors (TCR) or killer cell Ig-like receptors (KIR) may be accompanied by considerable changes in the conformation of selected residues or even entire loops within TCR or KIR, conformational changes between receptor-bound and -unbound MHC class I molecules of comparable magnitude have not been observed so far. We have previously determined the structure of the MHC class I molecule HLA-A1 bound to a melanoma antigen-encoding gene (MAGE)-A1-derived peptide in complex with a recombinant antibody fragment with TCR-like specificity, Fab-Hyb3. Here, we compare the X-ray structure of HLA-A1:MAGE-A1 with that complexed with Fab-Hyb3 to gain insight into structural changes of the MHC molecule that might be induced by the interaction with the antibody fragment. Apart from the expulsion of several water molecules from the interface, Fab-Hyb3 binding results in major rearrangements (up to 5.5 Å ) of heavy chain residues Arg65, Gln72, Arg145, and Lys146. Residue 65 is frequently and residues 72 and 146 are occasionally involved in TCR binding-induced conformational changes, as revealed by a comparison with MHC class I structures in TCR-liganded and -unliganded forms. On the other hand, residue 145 is subject to a reorientation following engagement of HLA-Cw4 and KIR2DL1. Therefore, conformational changes within the HLA-A1:MAGE-A1:Fab-Hyb3 complex include MHC residues that are also involved in reorientations in complexes with natural ligands, pointing to their central importance for the peptide-dependent recognition of MHC molecules.

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T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I–bound peptide

Cited by 259 publications

References 65 publications

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

The Impact of a Large and Frequent Deletion in the Human TCR β Locus on Antiviral Immunity

Conformational changes within the HLA‐A1:MAGE‐A1 complex induced by binding of a recombinant antibody fragment with TCR‐like specificity

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