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

doi:10.1016/j.cell.2014.08.042

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 journal › Article › peer-review

122 Scopus citations

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.

Original language	English
Pages (from-to)	333-345
Number of pages	13
Journal	Cell
Volume	159
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2014.08.042
State	Published - 9 Oct 2014
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Inc.

Funding

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.

Funders	Funder number
TerraIncognita
National Institutes of Health	R01DK095077, BB/H001085/1, P01AI071195, U19AI109858
National Institute of Allergy and Infectious Diseases	P01AI091580
Seventh Framework Programme
Biotechnology and Biological Sciences Research Council
European Commission	1-P01-AI091580
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

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Stepanek, O., Prabhakar, A. S., Osswald, C., King, C. G., Bulek, A., Naeher, D., Beaufils-Hugot, M., Abanto, M. L., Galati, V., Hausmann, B., Lang, R., Cole, D. K., Huseby, E. S., Sewell, A. K., Chakraborty, A. K., & Palmer, E. (2014). Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance. Cell, 159(2), 333-345. https://doi.org/10.1016/j.cell.2014.08.042

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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.",

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AU - Cole, David K.

AU - Huseby, Eric S.

AU - Sewell, Andrew K.

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AU - Palmer, Ed

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

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