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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2014
Author 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,
Project The role of TCR affinity in CD4+ T cell asymmetric division and differentiation
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Original article (peer-reviewed)

Journal Cell
Volume (Issue) 159(2)
Page(s) 333 - 45
Title of proceedings Cell
DOI 10.1016/j.cell.2014.08.042

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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