Correlation Between the Number of T Cell Receptors Required for T Cell Activation and TCR–Ligand Affinity

Schodin, Beth A.; Tsomides, Theodore J.; Kranz, David M.

doi:10.1016/s1074-7613(00)80490-2

Cited by 93 publications

(69 citation statements)

References 47 publications

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“…This conclusion favors the concept of T cell activation by an increasing number of receptor ligands (9), rather than the concept of serial triggering of few receptor molecules (10) to generate efficient T cell activation. As a cautionary note, the immunoreceptors used in this study have Ab-derived binding domains for MHCindependent recognition, which bind to Ag with higher affinity than TCRs whose affinity for MHC-bound peptide ligands is generally several orders of magnitude lower.…”

Section: Discussionmentioning

confidence: 80%

T Cell Activation by Antibody-Like Immunoreceptors: Increase in Affinity of the Single-Chain Fragment Domain above Threshold Does Not Increase T Cell Activation against Antigen-Positive Target Cells but Decreases Selectivity

Chmielewski

Hombach

Heuser

et al. 2004

The Journal of Immunology

235

223

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Chimeric TCRs with an Ab-derived binding domain confer predefined specificity and MHC-independent target binding to T cells for use in adoptive immunotherapy. We investigated the impact of receptor binding affinity on the activation of grafted T cells. A series of anti-ErbB2 single-chain fragment binding domains with a Kd ranging from 3.2 × 10−7 to 1.5 × 10−11 M was linked to CD3ζ-derived immunoreceptors and expressed in human PBL. Solid phase bound ErbB2 protein triggered activation of receptor-grafted T cells in a dose-dependent manner. The activation threshold inversely correlated with the affinity of the receptor binding domain. The maximum level of cellular activation, however, was the same and independent of the binding affinity. Upon binding to ErbB2+ cells, T cells grafted with immunoreceptors carrying a single-chain fragment of Kd < 10−8 M were activated in a similar fashion against cells with different amounts of ErbB2 on the surface. T cells with a low affinity receptor (Kd > 10−8 M), however, were activated exclusively by cells with high amounts of ErbB2. In conclusion, recombinant immunoreceptors of higher affinity do not necessarily induce a more potent activation of T cells than low affinity immunoreceptors, but the higher affinity immunoreceptors exhibit less discrimination between target cells with high or low Ag expression levels.

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Section: Discussionmentioning

confidence: 80%

T Cell Activation by Antibody-Like Immunoreceptors: Increase in Affinity of the Single-Chain Fragment Domain above Threshold Does Not Increase T Cell Activation against Antigen-Positive Target Cells but Decreases Selectivity

Chmielewski

Hombach

Heuser

et al. 2004

The Journal of Immunology

235

223

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“…We observed a diminution of V␤3 hi DP thymocytes during fetal thymic organ culture with GGQM and GEEK (data not shown), although these peptides allow maturation of T cells as evidenced by the CD4 SP thymocyte population. Mature T cells commonly express 30,000-100,000 TCRs, yet very few TCRs are actually required for activation and induction of effector functions by strong agonists (42,43). Because of this large receptor reserve, T cells seem to be a functional model of the spare receptor theory.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of peripheral T cell responses from thymocyte negative selection by weak agonists supports a spare receptor model of T cell activation

McNeil

Evavold

2002

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

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We have focused on stability of the peptide-MHC complex as a determining factor of ligand potency for thymocytes and peripheral CD4 ؉ T cell responses. MHC variant peptides that have low affinities and fast dissociation rates are different in that they stimulate proliferation and cytolysis of mature T cells (classifying the variant peptides as weak agonists) but do not induce thymocyte negative selection. The MHC variant weak agonists require significant receptor reserve, because decreasing the level of T cell receptor on mature T cells blocks the proliferative response. These results demonstrate that peripheral T cells are more sensitive to MHC variant ligands by virtue of increased T cell receptor expression; in addition, the data support a T cell model of the spare receptor theory.T he pivotal interaction between T cell receptor (TCR)-peptide-MHC ternary complexes mediates the development and activation of T cells. Mature T cells respond to antigenic peptides that can induce variable responses. Altered peptide ligands (APLs) are analog peptides with substitutions at TCR contact residues that have no change in affinity for the MHC molecule, and can be classified according to their ability to activate T cells, from agonist to partial agonist to antagonist to null (1-3). Investigation of the interactions of APLs with TCR has correlated dissociation, a kinetic parameter of peptide-MHC interaction, with the resulting T cell response (4-8). TCRs that dissociate very quickly from peptide-MHC ligands may result in no response, whereas ligands that bind for an extended duration lead to activation of the T cell. These data support the kinetic discrimination or kinetic proofreading models that suggest that the half-life of the interaction between peptide-MHC and TCR may determine the agonist or antagonist properties of a ligand (9, 10). A recent article expanded this model to state that any TCR half-life above or below an optimal dwell time, or length of TCR-peptide-MHC interaction, results in poor activation of the T cell (11). Because of the focus on classic APL with amino acid changes at TCR contacts, none of these models specifically address the effect of variation in the kinetics of peptide-MHC interactions on the potency of ligand and the resulting T cell response.Thymocytes, like peripheral T cells, are exquisitely sensitive to subtle changes in the peptide sequence. Early experiments with fetal thymic organ culture as a model for selection indicated that antagonists, weak agonists, and partial agonists induce positive selection of CD8 thymocytes (12-14), whereas CD4 T cell antagonists induce negative selection (15,16). Together, these data imply that thymocytes are more sensitive in that they respond by positive͞negative selection to APLs that fail to activate peripheral T cells. This increased sensitivity is consistent with the requirement of thymocytes to interact with self-peptide MHC complexes during selection to generate a T cell repertoire that responds to foreign antigen yet is tolerant to self (17-19).Th...

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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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Correlation Between the Number of T Cell Receptors Required for T Cell Activation and TCR–Ligand Affinity

Cited by 93 publications

References 47 publications

T Cell Activation by Antibody-Like Immunoreceptors: Increase in Affinity of the Single-Chain Fragment Domain above Threshold Does Not Increase T Cell Activation against Antigen-Positive Target Cells but Decreases Selectivity

T Cell Activation by Antibody-Like Immunoreceptors: Increase in Affinity of the Single-Chain Fragment Domain above Threshold Does Not Increase T Cell Activation against Antigen-Positive Target Cells but Decreases Selectivity

Dissociation of peripheral T cell responses from thymocyte negative selection by weak agonists supports a spare receptor model of T cell activation

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

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