Quantitative Analysis of the Contribution of TCR/pepMHC Affinity and CD8 to T Cell Activation

Holler, Phillip D.; Kranz, David M.

doi:10.1016/s1074-7613(03)00019-0

Cited by 331 publications

(387 citation statements)

References 59 publications

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“…This point has perhaps not been given sufficient weight in many previous studies, possibly because most analyses on series of APLs have dealt with single amino acid variants of the antigenic peptide. However, its importance in determining the efficacy of a pMHC ligand has recently been shown in another TCR-pMHC system (13). Also, it has been noted that anomalies in the off-rate: biological response relationship are frequently seen in series of APLs that differ in MHC-interaction residues (8,10,11).…”

Section: Discussionmentioning

confidence: 99%

“…Some recent evidence consistent with serial triggering has been presented, where longer half-lives of complexes resulted in lower T cell activation than complexes with intermediate half-lives (7). However, a study where TCR affinity was greatly increased by mutagenesis showed increased T cell reactivity (13). This result argues strongly against serial triggering.…”

mentioning

confidence: 99%

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TCR Binding Kinetics Measured with MHC Class I Tetramers Reveal a Positive Selecting Peptide with Relatively High Affinity for TCR

Holmberg

Mariathasan

Ohteki

et al. 2003

The Journal of Immunology

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The interaction between TCR and peptide-MHC (pMHC) complexes is crucial for the activation of T cells as well as for positive and negative selection in the thymus. The kinetics and affinity of this interaction and the densities of TCR and pMHC complexes on the cell surface are determining factors for different outcomes during thymic selection. In general, it is thought that agonist pMHC, which cause negative selection, have higher affinities and, in particular, slower off-rates than partial or weak agonists and antagonists, which cause positive selection. In this study, we have used pMHC tetramers to investigate the kinetics of TCR-pMHC interaction for agonist, weak agonist, and antagonist ligands of the anti-lymphocytic choriomeningitis virus P14 TCR. Kinetics determined on the cell surface may be biologically more relevant than methods using soluble proteins. We can distinguish between agonists and weak agonists or antagonists based on the half-life and the avidity of tetramer-TCR interaction. Furthermore, we show that a weak agonist self-peptide that positively selects P14 TCR+ thymocytes has a tetramer half-life and avidity only slightly weaker than strong agonists. We show that, in fact, it can act as quite a strong agonist, but that its poor ability to stabilize MHC causes it instead to have a weak agonist phenotype.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

TCR Binding Kinetics Measured with MHC Class I Tetramers Reveal a Positive Selecting Peptide with Relatively High Affinity for TCR

Holmberg

Mariathasan

Ohteki

et al. 2003

The Journal of Immunology

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“…Because the affinity of TCR/pMHC interaction is mainly controlled by its rate of dissociation (44), tetramer decay assays were performed to compare the stability of A2 and A2K b tetramer binding. Experiments were conducted using the NY-ESO-1 157-165 CTL lines H5 (Fig.…”

Section: Stability Of Tetramer Binding To Ctl Is Enhanced By the Presmentioning

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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“…In physiological T-cell activation, the activation efficiency correlates with the T-cell receptor (TCR) avidity to the cognate peptide-major histocompatibility complex (MHC) complex. [14][15][16][17][18] Optimal CD28 costimulation is provided by high-avidity engagement by dimeric B7.1 expressed on APCs, followed by dimer dissociation that facilitates downregulaton of CD28 and B7.1 internalization. 19 CD28 costimulation induces at least two independent activation pathways: one is integrated with TCR signalling in the context of synapse formation and is mediated through transcriptional enhancement and the second is mediated through increasing mRNA stability.…”

Section: Introductionmentioning

confidence: 99%

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

2010

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Adoptive immunotherapy of cancer using chimeric antigen receptor (CAR)-engineered T cells with redirected specificity showed efficacy in recent trials. In preclinical models, 'second-generation' CARs with CD28 costimulatory domain in addition to CD3z performed superior in redirecting T-cell effector functions and survival. Whereas CD28 costimulation sustains physiological T-cell receptor (TCR)-CD3 activation of naïve T cells, the impact of CD28 cosignalling on the threshold of CAR-mediated activation of pre-stimulated T cells without B7-CD28 recruitment remained unclear. Using CARs of different binding affinities, but same epitope specificity, we demonstrate that CD28 cosignalling neither lowered the antigen threshold nor the binding affinity for redirected T-cell activation. 'Affinity ceiling' above which increase in affinity does not increase T-cell activation was not altered. Accordingly, redirected tumor cell killing depended on the binding affinity but was likewise effective for CD3z and CD28-CD3z CARs. In contrast to CD3z, CD28-CD3z CAR-driven activation was not increased further by CD28-B7 engagement. However, CD28 cosignalling, which is required for interleukin-2 induction could not be replaced by high-affinity CD3z CAR binding or high-density antigen engagement. We conclude that CD28 CAR cosignalling does not alter the activation threshold but redirects T-cell effector functions.

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Quantitative Analysis of the Contribution of TCR/pepMHC Affinity and CD8 to T Cell Activation

Cited by 331 publications

References 59 publications

TCR Binding Kinetics Measured with MHC Class I Tetramers Reveal a Positive Selecting Peptide with Relatively High Affinity for TCR

TCR Binding Kinetics Measured with MHC Class I Tetramers Reveal a Positive Selecting Peptide with Relatively High Affinity for TCR

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

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

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