Coreceptor Scanning by the T Cell Receptor Provides a Mechanism for T Cell Tolerance
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Chakraborty_Coreceptor scanning.pdf
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Author(s)
Stepanek, Ondrej
Prabhakar, Arvind S.
Osswald, Celine
King, Carolyn G.
Bulek, Anna
Naeher, Dieter
Beaufils-Hugot, Marina
Abanto, Michael L.
Galati, Virginie
Hausmann, Barbara
Date Issued
October 2014
Journal
Cell
Publisher
Elsevier
Citation
Stepanek, Ondrej, Arvind S. Prabhakar, Celine Osswald, Carolyn G. King, Anna Bulek, Dieter Naeher, Marina Beaufils-Hugot, et al. “Coreceptor Scanning by the T Cell Receptor Provides a Mechanism for T Cell Tolerance.” Cell 159, no. 2 (October 2014): 333–345.
Version
Author's final manuscript
Abstract
In the thymus, high-affinity, self-reactive thymocytes are eliminated from the pool of developing T cells, generating central tolerance. Here, we investigate how developing T cells measure self-antigen affinity. We show that very few CD4 or CD8 coreceptor molecules are coupled with the signal-initiating kinase, Lck. To initiate signaling, an antigen-engaged T cell receptor (TCR) scans multiple coreceptor molecules to find one that is coupled to Lck; this is the first and rate-limiting step in a kinetic proofreading chain of events that eventually leads to TCR triggering and negative selection. MHCII-restricted TCRs require a shorter antigen dwell time (0.2 s) to initiate negative selection compared to MHCI-restricted TCRs (0.9 s) because more CD4 coreceptors are Lck-loaded compared to CD8. We generated a model (Lck come&stay/signal duration) that accurately predicts the observed differences in antigen dwell-time thresholds used by MHCI- and MHCII-restricted thymocytes to initiate negative selection and generate self-tolerance.
MIT Department
Institute for Medical Engineering and Science
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Physics
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.cell.2014.08.042
