Allelic polymorphism in the T cell receptor and its impact on immune responses

Gras, Stéphanie; Chen, Zhenjun; Miles, John J.; Liu, Yu Chih; Bell, Melissa J.; Sullivan, Lucy C.; Kjer‐Nielsen, Lars; Brennan, Rebekah; Burrows, Jacqueline M.; Neller, Michelle A.; Khanna, Rajiv; Purcell, Anthony W.; Brööks, Andrëw G.; McCluskey, James; Rossjohn, Jamie; Burrows, Scott R.

doi:10.1084/jem.20100603

Cited by 87 publications

(105 citation statements)

References 56 publications

(100 reference statements)

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“…Analyte production was calculated by comparing test samples to standard curves using FCAP Array Software (Soft Flow Hungary, Pécs, Hungary). As previously observed, the TK3 CTL clone recognized the HPVG-A4 variant comparably to the wild type (WT) HPVG epitope in the context of self-HLA-B*35:01, whereas the HPVG-Q5 and HPVG-D5 variants showed markedly diminished TK3 recognition (20). Next, we performed a cytotoxicity assay using HLA-B*35:08 ϩ target cells in the presence of the HPVG peptide and its three variants.…”

Section: Methodssupporting

confidence: 57%

“…2), the absolute cytokine/granzyme A levels ( Fig. 2) enabled efficient killing of the HLA-B*35:01 target cells presenting the HPVG-A4 peptide (20). However, the concentrations of these analytes produced by TK3 in the presence of the HPVG-D5 and HPVG-Q5 variants and HLA-B*35:01 ϩ -target cells were markedly diminished.…”

Section: Hla Polymorphism Affects Epitope Recognition By the Tk3 T Cementioning

confidence: 95%

“…Expression, Refolding, and Purification of Recombinant TCR and pHLA-The production of the TK3 TCR, HLA-B*35 allomorphs in complex with HPVG and its variants, were previously described (20). Briefly, individual components of the TCR and HLA molecules were expressed in BL21 Escherichia coli cells as inclusion bodies and solubilized in 8 M urea buffer containing 10 mM Tris, pH 8, 0.5 mM Na-EDTA, and 1 mM dithiothreitol.…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, it has been suggested that variation in the latent nuclear protein EBNA-1 is linked to the development of EBV-associated diseases (18). One EBNA-1 epitope that contains known mutations is HPVG (HPVGEADYFEY), which has been identified in EBV strains infecting Caucasians (19,20). The EBV strains infecting Chinese individuals (21,22) encode a variation at position 5 of this epitope, with an Asp replacing the Glu (HPVG-D5), whereas in some type 1 EBV isolates (19,23) a glutamine is encoded at position 5 (HPVG-Q5).…”

mentioning

confidence: 99%

“…Previously we investigated the CTL response to the HPVG determinant in HLA-B*35:01 ϩ individuals and the mode of recognition by a prototypic TRBV9 ϩ public TCR, termed TK3. Although the TK3 clone could recognize both HLA-B*35:01 and HLA-B*35:08 presenting the HPVG peptide, it exhibited much higher reactivity toward HLA-B*35:01 (20). However, the molecular basis of the TK3 HLA allomorph specificity was unclear.…”

mentioning

confidence: 99%

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A Molecular Basis for the Interplay between T Cells, Viral Mutants, and Human Leukocyte Antigen Micropolymorphism

Liu¹,

Chen²,

Neller³

et al. 2014

Journal of Biological Chemistry

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Section: Methodssupporting

confidence: 57%

Section: Hla Polymorphism Affects Epitope Recognition By the Tk3 T Cementioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A Molecular Basis for the Interplay between T Cells, Viral Mutants, and Human Leukocyte Antigen Micropolymorphism

Liu¹,

Chen²,

Neller³

et al. 2014

Journal of Biological Chemistry

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Characterization of Human Mucosal‐associated Invariant T (MAIT) Cells

Souter

Loh

et al. 2019

CP in Immunology

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Mucosal‐associated invariant T (MAIT) cells are a subset of unconventional T cells restricted by the major histocompatibility complex (MHC) class I–like molecule MHC‐related protein 1 (MR1). MAIT cells are found throughout the body, especially in human blood and liver. Unlike conventional T cells, which are stimulated by peptide antigens presented by MHC molecules, MAIT cells recognize metabolite antigens derived from an intermediate in the microbial biosynthesis of riboflavin. MAIT cells mediate protective immunity to infections by riboflavin‐producing microbes via the production of cytokines and cytotoxicity. The discovery of stimulating MAIT cell antigens allowed for the development of an analytical tool, the MR1 tetramer, that binds specifically to the MAIT T cell receptor (TCR) and is becoming the gold standard for identification of MAIT cells by flow cytometry. This article describes protocols to characterize the phenotype of human MAIT cells in blood and tissues by flow cytometry using fluorescently labeled human MR1 tetramers alongside antibodies specific for MAIT cell markers. © 2019 by John Wiley & Sons, Inc. The main protocols include: Basic Protocol 1: Determining the frequency and steady‐state surface phenotype of human MAIT cells Basic Protocol 2: Determining the activation phenotype of human MAIT cells in blood Basic Protocol 3: Characterizing MAIT cell TCRs using TCR‐positive reporter cell lines Alternate protocols are provided for determining the absolute number, transcription factor phenotype, and TCR usage of human MAIT cells; and determining activation phenotype by staining for intracellular markers, measuring secreted cytokines, and measuring fluorescent dye dilution due to proliferation. Additional methods are provided for determining the capacity of MAIT cells to produce cytokine independently of antigen using plate‐bound or bead‐immobilized CD3/CD28 stimulation; and determining the MR1‐Ag dependence of MAIT cell activation using MR1‐blocking antibody or competitive inhibition. For TCR‐positive reporter cell lines, methods are also provided for evaluating the MAIT TCR‐mediated MR1‐Ag response, determining the capacity of the reporter lines to produce cytokine independently of antigen, determining the MR1‐Ag dependence of the reporter lines, and evaluating the MR1‐Ag response of the reporter lines using IL‐2 secretion. Support Protocols describe the preparation of PBMCs from human blood, the preparation of single‐cell suspensions from tissue, the isolation of MAIT cells by FACS and MACS, cloning MAIT TCRα and β chain genes and MR1 genes for transduction, generating stably and transiently transfected cells lines, generating a stable MR1 knockout antigen‐presenting cell line, and generating monocyte‐derived dendritic cells.

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Unexpected T‐cell recognition of an altered peptide ligand is driven by reversed thermodynamics

et al. 2012

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The molecular basis underlying T-cell recognition of MHC molecules presenting altered peptide ligands is still not well-established. A hierarchy of T-cell activation by MHC class I-restricted altered peptide ligands has been defined using the T-cell receptor P14 specific for H-2D b in complex with the immunodominant lymphocytic choriomeningitis virus peptide gp33 (KAVYNFATM). While substitution of tyrosine to phenylalanine (Y4F) or serine (Y4S) abolished recognition by P14, the TCR unexpectedly recognized H-2D b incomplex with the alanine-substituted semiagonist Y4A, which displayed the most significant structural modification. The observed functional hierarchy gp33 > Y4A > Y4S = Y4F was neither due to higher stabilization capacity nor to differences in structural conformation. However, thermodynamic analysis demonstrated that while recognition of the full agonist H-2D b /gp33 was strictly enthalpy driven, recognition of the weak agonist H-2D b /Y4A was instead entropy driven with a large reduction in the favorable enthalpy term. The fourfold larger negative heat capacity derived for the interaction of P14 with H-2D b /gp33 compared with H-2D b /Y4A can possibly be explained by higher water entrapment at the TCR/MHC interface, which is also consistent with the measured opposite entropy contributions for the interactions of P14 with both MHCs. In conclusion, this study demonstrates that P14 makes use of different strategies to adapt to structural modifications in the MHC/peptide complex.Keywords: MHC r Molecular immunology r Protein-protein interactions r Structural biology r TCR Supporting Information available online IntroductionRecognition of MHC molecules bound to peptides (pMHCs) by TCRs is a critical step for the initiation of T-cell responses.Correspondence: Dr. Adnane Achour e-mail: adnane.achour@ki.seAlthough this interaction is considered as highly specific, it is now well established that TCRs may also recognize other pMHCs [1][2][3][4][5][6].The activation of T cells can be modulated by alterations in the presented peptides [7,8], the CDR loops of the TCR [9] and the * These authors contributed equally to this work. * * These authors shared seniour authorship.C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 2990 Molecular immunology 2991 α 1 α 2 -domains of MHC molecules [10][11][12][13]. Depending on the quality of the triggered immune responses, APLs can be classified as: (i) agonists with the capacity to trigger a full range of T-cell activation events including TCR downregulation, cytokine production, granule release, and proliferation; (ii) weak agonists with the ability to induce lower magnitudes of TCR activation; (iii) partial agonists that may evoke a fraction of the events that characterize full T-cell activation; (iv) null peptides with no effect; or (v) antagonists that inhibit immune responses triggered by agonists. The slowly increasing number of TCR/pMHC crystal structures has started to provide important insights into a few common struc...

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Allelic polymorphism in the T cell receptor and its impact on immune responses

Cited by 87 publications

References 56 publications

A Molecular Basis for the Interplay between T Cells, Viral Mutants, and Human Leukocyte Antigen Micropolymorphism

A Molecular Basis for the Interplay between T Cells, Viral Mutants, and Human Leukocyte Antigen Micropolymorphism

Characterization of Human Mucosal‐associated Invariant T (MAIT) Cells

Unexpected T‐cell recognition of an altered peptide ligand is driven by reversed thermodynamics

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