To assess the roles of serial engagement and kinetic proofreading in T cell receptor (TCR) internalization, we have developed a mathematical model of this process. Our determination of TCR down-regulation for an array of TCR mutants, interpreted in the context of the model, has provided new information about peptide-induced TCR internalization. The amount of TCR down-regulation increases to a maximum value and then declines as a function of the half-life of the bond between the TCR and peptide–major histocompatibility complex (pMHC). The model shows that this behavior, which reflects competition between serial engagement and kinetic proofreading, arises only if it is postulated that activated TCRs remain marked for internalization after dissociation from pMHC. The model also predicts that because of kinetic proofreading, the range of TCR-pMHC–binding half-lives required for T cell activation depends on the concentrations and localization of intracellular signaling molecules. We show here that kinetic proofreading provides an explanation for the different requirements for activation observed in naïve and memory T cells.
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Supported by National Institutes of Health grant GM35556 and National Science Foundation grant MCB9723897 and performed, in part, under the auspices of the U.S. Department of Energy. A. M. K. is supported by the Helen Hay Whitney Foundation.
*Note: In the AOP version of this article, the second sentence of the legend to Fig. 4 contained an error. This sentence should read: "Each point represents the indicated TCR-pMHC pair: 1, V98D- Kb-VSV; 2, V98L-Kb-VSV; 3, N30.7-KbA158T-VSV; 4, G99A-KbA158T-VSV; 5, G97/99A-KbA158T-VSV; 6, G97A-KbA158T-VSV; 7, N30.7- Kb-VSV; 8, G97A-Kb-VSV; 9, G97/99A- Kb-VSV; 10, G99A-Kb-VSV." This error has been corrected in the HTML version but appears incorrectly in print. A printed corrigendum will appear in the November 2002 issue of Nature Immunology, when the PDF version available online will also be appended.
The authors declare no competing financial interests.
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Coombs, D., Kalergis, A., Nathenson, S. et al. Activated TCRs remain marked for internalization after dissociation from pMHC. Nat Immunol 3, 926–931 (2002). https://doi.org/10.1038/ni838
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