Nature Immunology3, 926 - 931 (2002)
Published online: 9 September 2002; Corrected online: 09 October 2002 ; Corrected online: 12 September 2002 | doi:10.1038/ni838
There is a Corrigendum (November 2002) associated with this Article.
Activated TCRs remain marked for internalization after dissociation from pMHC
Daniel Coombs1, Alexis M. Kalergis2, Stanley G. Nathenson3, Carla Wofsy1, 4
& Byron Goldstein1
1
Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
2
Laboratory of Molecular Genetics and Immunology, Rockefeller University, 1230 York Avenue, Box 98, New York, NY 10021-6399, USA.
3
Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Chanin Building #407, Bronx, NY 10461, USA.
4
Department of Mathematics and Statistics, University of New Mexico, Albuquerque, NM 87131, USA.
Correspondence should be addressed to Byron Goldstein bxg@lanl.gov
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.
