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Activated TCRs remain marked for internalization after dissociation from pMHC
Daniel Coombs1, Alexis M Kalergis, Stanley G Nathenson
1Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Nature Immunology
|September 24, 2002
Summary
Mathematical modeling reveals how T cell receptor (TCR) internalization depends on peptide-MHC binding half-life, highlighting the roles of serial engagement and kinetic proofreading in T cell activation.
Area of Science:
- Immunology
- Computational Biology
- Cell Signaling
Background:
- T cell receptor (TCR) signaling is crucial for adaptive immunity.
- Understanding TCR internalization mechanisms is key to deciphering T cell activation thresholds.
Purpose of the Study:
- To investigate the roles of serial engagement and kinetic proofreading in TCR internalization.
- To elucidate the relationship between TCR-pMHC binding kinetics and TCR down-regulation.
Main Methods:
- Development of a mathematical model for TCR internalization.
- Analysis of TCR down-regulation across various TCR mutants.
- Interpretation of experimental data within the framework of the mathematical model.
Main Results:
- TCR down-regulation exhibits a non-monotonic dependence on TCR-pMHC bond half-life.
- This behavior is explained by the interplay of serial engagement and kinetic proofreading.
- Kinetic proofreading influences the TCR-pMHC binding half-life range for T cell activation.
Conclusions:
- Activated TCRs must remain marked for internalization post-dissociation for observed down-regulation patterns.
- Kinetic proofreading explains differential activation requirements between naive and memory T cells.
- The model provides insights into peptide-MHC-mediated T cell signaling dynamics.