Dependence of T cell antigen recognition on T cell receptor-peptide MHC confinement time.
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.
Aleksic
Milos
M
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
Dushek
Omer
O
Zhang
Hao
H
Shenderov
Eugene
E
Chen
Ji-Li
JL
Cerundolo
Vincenzo
V
Coombs
Daniel
D
van der Merwe
P Anton
PA
D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D018448:Models, Immunological; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection
D015789:HLA-A2 Antigen; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C504237:peptide NY-ESO-1 157-165; D007371:Interferon-gamma