Dependence of T Cell Antigen Recognition on T Cell Receptor-Peptide MHC Confinement Time

Milos Aleksic; Omer Dushek; Hao Zhang; Eugene Shenderov; Ji Li Chen; Vincenzo Cerundolo; Daniel Coombs; P. Anton van der Merwe

doi:10.1016/j.immuni.2009.11.013

Dependence of T Cell Antigen Recognition on T Cell Receptor-Peptide MHC Confinement Time

Milos Aleksic, Omer Dushek, Hao Zhang, Eugene Shenderov, Ji Li Chen, Vincenzo Cerundolo, Daniel Coombs, P. Anton van der Merwe

Research output: Contribution to journal › Article › peer-review

142 Scopus citations

Abstract

T cell receptor (TCR) binding to diverse peptide-major histocompatibility complex (pMHC) ligands results in various degrees of T cell activation. Here we analyze which binding properties of the TCR-pMHC interaction are responsible for this variation in pMHC activation potency. We have analyzed activation of the 1G4 cytotoxic T lymphocyte clone by cognate pMHC variants and performed thorough correlation analysis of T cell activation with 1G4 TCR-pMHC binding properties measured in solution. We found that both the on rate (k_on) and off rate (k_off) contribute to activation potency. Based on our results, we propose a model in which rapid TCR rebinding to the same pMHC after chemical dissociation increases the effective half-life or "confinement time" of a TCR-pMHC interaction. This confinement time model clarifies the role of k_on in T cell activation and reconciles apparently contradictory reports on the role of TCR-pMHC binding kinetics and affinity in T cell activation.

Original language	English (US)
Pages (from-to)	163-174
Number of pages	12
Journal	Immunity
Volume	32
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2009.11.013
State	Published - Feb 26 2010
Externally published	Yes

Keywords

MOLIMMUNO

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2009.11.013

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title = "Dependence of T Cell Antigen Recognition on T Cell Receptor-Peptide MHC Confinement Time",

abstract = "T cell receptor (TCR) binding to diverse peptide-major histocompatibility complex (pMHC) ligands results in various degrees of T cell activation. Here we analyze which binding properties of the TCR-pMHC interaction are responsible for this variation in pMHC activation potency. We have analyzed activation of the 1G4 cytotoxic T lymphocyte clone by cognate pMHC variants and performed thorough correlation analysis of T cell activation with 1G4 TCR-pMHC binding properties measured in solution. We found that both the on rate (kon) and off rate (koff) contribute to activation potency. Based on our results, we propose a model in which rapid TCR rebinding to the same pMHC after chemical dissociation increases the effective half-life or {"}confinement time{"} of a TCR-pMHC interaction. This confinement time model clarifies the role of kon in T cell activation and reconciles apparently contradictory reports on the role of TCR-pMHC binding kinetics and affinity in T cell activation.",

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author = "Milos Aleksic and Omer Dushek and Hao Zhang and Eugene Shenderov and Chen, {Ji Li} and Vincenzo Cerundolo and Daniel Coombs and {van der Merwe}, {P. Anton}",

note = "Funding Information: We thank D. Shepherd for the supply of the 1G4 TCR expression plasmid and J. Byrne for the help with protein expression. We would also like to thank the reviewers for their constructive criticism. This work was supported by Cancer Research UK, the Medical Research Council (UK), the National Sciences and Engineering Research Council (Canada), and the Mathematics of Information Technology and Complex Systems National Centre of Excellence (Canada). ",

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AU - Aleksic, Milos

AU - Dushek, Omer

AU - Zhang, Hao

AU - Shenderov, Eugene

AU - Chen, Ji Li

AU - Cerundolo, Vincenzo

AU - Coombs, Daniel

AU - van der Merwe, P. Anton

N1 - Funding Information: We thank D. Shepherd for the supply of the 1G4 TCR expression plasmid and J. Byrne for the help with protein expression. We would also like to thank the reviewers for their constructive criticism. This work was supported by Cancer Research UK, the Medical Research Council (UK), the National Sciences and Engineering Research Council (Canada), and the Mathematics of Information Technology and Complex Systems National Centre of Excellence (Canada).

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Y1 - 2010/2/26

N2 - T cell receptor (TCR) binding to diverse peptide-major histocompatibility complex (pMHC) ligands results in various degrees of T cell activation. Here we analyze which binding properties of the TCR-pMHC interaction are responsible for this variation in pMHC activation potency. We have analyzed activation of the 1G4 cytotoxic T lymphocyte clone by cognate pMHC variants and performed thorough correlation analysis of T cell activation with 1G4 TCR-pMHC binding properties measured in solution. We found that both the on rate (kon) and off rate (koff) contribute to activation potency. Based on our results, we propose a model in which rapid TCR rebinding to the same pMHC after chemical dissociation increases the effective half-life or "confinement time" of a TCR-pMHC interaction. This confinement time model clarifies the role of kon in T cell activation and reconciles apparently contradictory reports on the role of TCR-pMHC binding kinetics and affinity in T cell activation.

AB - T cell receptor (TCR) binding to diverse peptide-major histocompatibility complex (pMHC) ligands results in various degrees of T cell activation. Here we analyze which binding properties of the TCR-pMHC interaction are responsible for this variation in pMHC activation potency. We have analyzed activation of the 1G4 cytotoxic T lymphocyte clone by cognate pMHC variants and performed thorough correlation analysis of T cell activation with 1G4 TCR-pMHC binding properties measured in solution. We found that both the on rate (kon) and off rate (koff) contribute to activation potency. Based on our results, we propose a model in which rapid TCR rebinding to the same pMHC after chemical dissociation increases the effective half-life or "confinement time" of a TCR-pMHC interaction. This confinement time model clarifies the role of kon in T cell activation and reconciles apparently contradictory reports on the role of TCR-pMHC binding kinetics and affinity in T cell activation.

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Dependence of T Cell Antigen Recognition on T Cell Receptor-Peptide MHC Confinement Time

Abstract

Keywords

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