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Cell. 2014 Oct 9;159(2):333-45. doi: 10.1016/j.cell.2014.08.042. Epub 2014 Oct 2.

Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance.

Author information

1
Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. Electronic address: ondrej.stepanek@unibas.ch.
2
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
4
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
5
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
6
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science, Departments of Physics, Chemistry, and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, 400 Technology Square, Cambridge, MA 02139, USA.
7
Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. Electronic address: ed.palmer@unibas.ch.

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.

PMID:
25284152
PMCID:
PMC4304671
DOI:
10.1016/j.cell.2014.08.042
[Indexed for MEDLINE]
Free PMC Article

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