Coreceptor Scanning by the T Cell Receptor Provides a Mechanism for T Cell Tolerance
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; Lang, Rosemarie; Cole, David K.; Huseby, Eric S.; Sewell, Andrew K.; Chakraborty, Arup K.; Palmer, Ed; Prabhakar, Arvind S.; Chakraborty, Arup K.; ... Show more Show less
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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.
DepartmentInstitute 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
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.
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