The Impact of Duration versus Extent of TCR Occupancy on T Cell Activation

Rosette, Caridad; Werlen, Guy; Daniëls, Mark A.; Holman, Philmore O.; Alam, S. Munir; Travers, Paul; Gascoigne, Nicholas R. J.; Palmer, Ed; Jameson, Stephen C.

doi:10.1016/s1074-7613(01)00173-x

Cited by 216 publications

(254 citation statements)

References 52 publications

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“…However, preliminary comparisons of calculated data with experimental data obtained from the literature (6,19,22,23) have shown that this model was realistic. In this study, we have used this computer simulation choosing a set of initial parameters (agonistic peptide, cell sizes, and CD3 levels of expression) that are close to the conditions in vivo.…”

Section: Variability Of Cd3 Membrane Expression and T Cell Activationmentioning

confidence: 83%

“…If the number of p-MHC is restricted, serial engagement of TCR are possible (18)(19)(20). Further TCR/CD3 complexes need to be recruited from outside the synapse through surface transfer but this has to be completed during a short lag time (16,(21)(22)(23) to be efficient. Activation induces IL-2 production and membrane expression of the c chain of its receptor [CD25; (24)].…”

mentioning

confidence: 99%

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Variability of CD3 membrane expression and T cell activation capacity

Hentati

Gruy

Iobagiu

et al. 2009

Cytometry Part B Clinical

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Background: abT cells have a wide distribution of CD3 membrane density. The aim of this article was to evaluate the significance of the CD3 differential expression on T cell subsets. Analysis was performed on healthy donors and renal transplant patients by flow cytometry. The results obtained are: (1) CD3 expression was widely distributed (CV 5 38.3 6 3.1 to 43 6 2.3%). (2) The CD4, CD8, CD45 and forward scatter were similarly distributed. (3) The diversity of CD3 expression was directly related to the clonotypes: c9, non c9 from cdT cells and Vb clonotype from abT cells (e.g., Vb3FITC 7,980 6 1,628 Vb8PE: Vb20-FITC 11,768 6 1,510). (4) Using a computer simulation, we could confirm differential kinetics of T cell activation according to the initial parameters. Finally, in vitro activation was significantly higher on Vb8 and Vb9 (high CD3) compared with Vb2 and Vb3 (low CD3, P 5 0.040-0.0003).

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Section: Variability Of Cd3 Membrane Expression and T Cell Activationmentioning

confidence: 83%

mentioning

confidence: 99%

Variability of CD3 membrane expression and T cell activation capacity

Hentati

Gruy

Iobagiu

et al. 2009

Cytometry Part B Clinical

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“…The differences in affinity and half-life between agonists and antagonists are surprisingly small. It is also possible to find weak agonist ligands that activate through a gradual build-up of signals, culminating in full activation, but where the early points in the signaling cascade are not detectable (12). Similar models apply during thymic selection, where a long TCR-pMHC interaction leads to negative selection and shorter interactions give positive selection.…”

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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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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“…The half-life (t 1/2 ) of the TCR/pMHC interaction must be above certain threshold to allow productive TCR signaling, as proposed by the kinetic proofreading model (11). Several studies have provided evidence supporting this notion by showing that pMHC ligands with excessively short half-lives fail to complete the signaling cascade required for T-cell activation (14)(15)(16)(17).…”

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confidence: 99%

T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC

Carreño

Riquelme

González

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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T-cell activation results from productive T-cell receptor (TCR) engagement by a cognate peptide-MHC (pMHC) complex on the antigen presenting cell (APC) surface, a process leading to the polarization of the T-cell secretory machinery toward the APC interface. We have previously shown that the half-life of the TCR/ pMHC interaction and the density of pMHC on the APC are two parameters determining T-cell activation. However, whether the half-life of the TCR/pMHC interaction can modulate the efficiency of T-cell secretory machinery polarization toward an APC still remains unclear. Here, by using altered peptide ligands conferring different half-lives to the TCR/pMHC interaction, we have tested how this parameter can control T-cell polarization. We observed that only TCR/pMHC interactions with intermediate half-lives can promote the assembly of synapses that lead to T-cell activation. Strikingly, intermediate half-life interactions can be competed out by short half-life interactions, which can efficiently promote T-cell polarization and antagonize T-cell activation that was induced by activating intermediate half-life interactions. However, short TCR/ pMHC interactions fail at promoting phosphorylation of signaling molecules at the T-cell-APC contact interface, which are needed for T-cell activation. Our data suggest that although intermediate half-life pMHC ligands promote assembly of activating synapses, this process can be inhibited by short half-life antagonistic pMHC ligands, which promote the assembly of non activating synapses.immunological synapse | T-cell receptor | T-cell receptor half-life | dendritic cells

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The Impact of Duration versus Extent of TCR Occupancy on T Cell Activation

Cited by 216 publications

References 52 publications

Variability of CD3 membrane expression and T cell activation capacity

Variability of CD3 membrane expression and T cell activation capacity

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

T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC

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