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

Ondrej Stepanek, Arvind S. Prabhakar, Celine Osswald, Carolyn G. King, Anna Bulek, Dieter Naeher, Marina Beaufils-Hugot, Michael L. Abanto, Virginie Galati, Barbara Hausmann, Rosemarie Lang, David K. Cole, Eric S. Huseby, Andrew K. Sewell, Arup K. Chakraborty, Ed Palmer

Research output: Contribution to journalArticlepeer-review

119 Scopus citations


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.

Original languageEnglish
Pages (from-to)333-345
Number of pages13
Issue number2
StatePublished - 9 Oct 2014
Externally publishedYes

Bibliographical note

Funding Information:
We thank U. Schneider for animal husbandry and E. Traunecker and T. Krebs for cell sorting. This study was funded by grants to E.P. (310030-149972/1 and Synergia [SNF], Sybilla [EU FP7], and TerraIncognita [ERC]), A.K.C. (1-P01-AI091580 [NIH]), E.S.H. (R01-DK095077 [NIH]), and A.K.S. (BB/H001085/1 [BBSRC]). D.K.C. is a Wellcome Trust Career Development Fellow. A.K.S. is a Wellcome Trust Senior Investigator.

Publisher Copyright:
© 2014 Elsevier Inc.


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