Antagonism of cytotoxic T lymphocyte‐mediated lysis by natural HIV‐1 altered peptide ligands requires simultaneous presentation of agonist and antagonist peptides

Sewell, Andrew K.; Harcourt, Gillian; Goulder, Philip; Price, David A.; Phillips, Rodney E.

doi:10.1002/eji.1830270929

Cited by 58 publications

(104 citation statements)

References 27 publications

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“…The specificity of the line was confirmed by pMHCI tetramer staining. The 003 CTL clone specific for the HLA A2-restricted HIV-1 epitope SLYNTVATL (p17 Gag; residues 77-85) was isolated and maintained as previously described (11).…”

Section: B Cell Lines-lbl 721174 Cells T1 Cells and Epstein-barr Vmentioning

confidence: 99%

“…In addition, experiments in which B cells pulsed with either the HTLV-1 Tax [11][12][13][14][15][16][17][18][19] peptide or the influenza matrix 58 -66 peptide were stained with the irrelevant TCR tetramer failed to show detectable cross-staining with non-cognate ligand (Fig. 3).…”

mentioning

confidence: 99%

“…peptides derived from different pathogens, some of them exhibiting a degree of sequence similarity with HTLV-1 Tax [11][12][13][14][15][16][17][18][19] and influenza matrix 58 -66 at non-anchor residues. No nonspecific binding of TCR multimers to cells pulsed with any of these peptides was detected (Fig.…”

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confidence: 99%

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Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition

Laugel

Boulter

Lissin³

et al. 2005

Journal of Biological Chemistry

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The use of recombinant T cell receptors (TCRs) to target therapeutic interventions has been hindered by the naturally low affinity of TCR interactions with peptide major histocompatibility complex ligands. Here, we use multimeric forms of soluble heterodimeric ␣␤ TCRs for specific detection of target cells pulsed with cognate peptide, discrimination of quantitative changes in antigen display at the cell surface, identification of virusinfected cells, inhibition of antigen-specific cytotoxic T lymphocyte activation, and identification of cross-reactive peptides. Notably, the A6 TCR specific for the immunodominant HLA A2-restricted human T cell leukemia virus type 1 Tax 11-19 epitope bound to HLA A2-HuD 87-95 (K D 120 M by surface plasmon resonance), an epitope implicated as a causal antigen in the paraneoplastic neurological degenerative disorder anti-Hu syndrome. A mutant A6 TCR that exhibited dramatically increased affinity for cognate antigen (K D 2.5 nM) without enhanced cross-reactivity was generated; this TCR demonstrated potent biological activity even as a monomeric molecule. These data provide insights into TCR repertoire selection and delineate a framework for the selective modification of TCRs in vitro that could enable specific therapeutic intervention in vivo.Peptide major histocompatibility complex (pMHC) 1 antigens displayed on the surface of target cells are recognized by T cells via their specific T cell receptor (TCR) (1). The TCR coreceptors CD8 or CD4 bind to invariant domains of pMHC class I (pMHCI) or pMHC class II (pMHCII) and are known to facilitate the process of antigen recognition by T cells (2). Recent advances have enabled the generation of high quality soluble TCR, pMHCI, pMHCII, CD8, and CD4 proteins; these in turn have allowed the biophysical characterization of the interactions between these molecules. Accordingly, the TCR and CD4/8 co-receptors have been shown to have very low affinities (K D ϳ 10 Ϫ3 -10 Ϫ6 M) for cognate pMHC. Despite these low affinity interactions, however, the process of antigen engagement can initiate T cell recognition of antigen-presenting cells (APCs) bearing fewer than 10 copies of a specific pMHC complex (3, 4). The mechanisms by which these weak recognition events result in such exquisite sensitivity are not fully understood.The production of soluble recombinant ␣␤ T cell receptors has proved challenging. The main technical pitfall is heterodimeric instability in the absence of anchoring transmembrane domains and ␣/␤ pairing through an interchain disulfide bond. One of the commonest protein engineering strategies used in TCR studies to date has been the construction of singlechain TCRs. This technique, which takes advantage of the structural similarities between antibodies and TCRs, is based upon the single-chain Fv technology used to generate antibody fragments (5). In short, for the TCR it involves the cloning and expression of a unique chimerical open reading frame where the variable (V) ␣ and V␤ domains are paired with a protein linker (6, 7). Thes...

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Section: B Cell Lines-lbl 721174 Cells T1 Cells and Epstein-barr Vmentioning

confidence: 99%

mentioning

confidence: 99%

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Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition

Laugel

Boulter

Lissin³

et al. 2005

Journal of Biological Chemistry

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“…HIV-1 p17 Gag-specific clones C, D, and E (5C3, 5D3, and 5D8) were sorted from a healthy donor using tetramer, whereas clone F (clone 003) was derived from an HIV-1 patient by limiting dilution (42).…”

Section: Human Ctl Clonesmentioning

confidence: 99%

“…MIP-1␤ release was measured because this cytokine is a ligand for HIV-1 coreceptor CCR5, and has been shown to inhibit HIV-1 infection (47). High avidity clone F is the immunodominant clone from HIV-1-infected patient 003, and has been described extensively elsewhere (42). Lower avidity clones C, D, and E were isolated from an uninfected individual by A2 tetramer guided sorting.…”

Section: Cd8-null Tetramers Distinguish Between High Avidity and Low mentioning

confidence: 99%

High Avidity Antigen-Specific CTL Identified by CD8-Independent Tetramer Staining

Choi

Chen

Wooldridge

et al. 2003

The Journal of Immunology

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Tetrameric MHC/peptide complexes are important tools for enumerating, phenotyping, and rapidly cloning Ag-specific T cells. It remains however unclear whether they can reliably distinguish between high and low avidity T cell clones. In this report, tetramers with mutated CD8 binding site selectively stain higher avidity human and murine CTL capable of recognizing physiological levels of Ag. Furthermore, we demonstrate that CD8 binding significantly enhances the avidity as well as the stability of interactions between CTL and cognate tetramers. The use of CD8-null tetramers to identify high avidity CTL provides a tool to compare vaccination strategies for their ability to enhance the frequency of high avidity CTL. Using this technique, we show that DNA priming and vaccinia boosting of HHD A2 transgenic mice fail to selectively expand large numbers of high avidity NY-ESO-1157–165-specific CTL, possibly due to the large amounts of antigenic peptide delivered by the vaccinia virus. Furthermore, development of a protocol for rapid identification of high avidity human and murine T cells using tetramers with impaired CD8 binding provides an opportunity not only to monitor expansion of high avidity T cell responses ex vivo, but also to sort high avidity CTL clones for adoptive T cell transfer therapy.

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Inhibition of TCR triggering by a spectrum of altered peptide ligands suggests the mechanism for TCR antagonism

Bachmann¹,

Speiser

Zakarian

et al. 1998

Eur. J. Immunol.

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Understanding the parameters involved in T cell activation has been complicated by the discovery of partial T cell agonists. Altered peptide ligands (APL) have recently shown that different subsets of T cell responses can be selectively activated by certain peptides, which define a hierarchy of T cell activation. For cytotoxic T cells, this hierarchy ranges from sensitizing target cells for lysis through proliferation to effector cell induction. The degree of TCR down-regulation mediated by APL-MHC interactions correlates well with the induction of specific T cell effector functions. This suggests that the potential agonist response induced by a given peptide occurs at different triggering thresholds. To examine the relative agonist and antagonist functions of different peptides, we have investigated the ability of lymphocytic choriomeningitis virus glycoprotein-derived APL to induce or inhibit a range of effector functions in naive CD8+ T cells. By this, we have defined a hierarchy of peptides that display a range of properties from strong agonist to no agonist function. At each level, peptides that were ranked lower in this hierarchy were able to interfere or antagonize the induction of effector functions by higher ranking peptides. We have therefore shown that this spectrum of peptides ranging from strong to no agonist function has an inverse gradient from strong antagonist to no antagonist function. Moreover, the ability of the different peptides to inhibit TCR internalization correlated with their ranking within the hierarchy. These findings support the model that antagonists are effectively preventing TCR oligomerization and functional TCR triggering.

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Antagonism of cytotoxic T lymphocyte‐mediated lysis by natural HIV‐1 altered peptide ligands requires simultaneous presentation of agonist and antagonist peptides

Cited by 58 publications

References 27 publications

Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition

Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition

High Avidity Antigen-Specific CTL Identified by CD8-Independent Tetramer Staining

Inhibition of TCR triggering by a spectrum of altered peptide ligands suggests the mechanism for TCR antagonism

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