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

Research paper by Ondrej O Stepanek, Arvind S AS Prabhakar, Celine C Osswald, Carolyn G CG King, Anna A Bulek, Dieter D Naeher, Marina M Beaufils-Hugot, Michael L ML Abanto, Virginie V Galati, Barbara B Hausmann, Rosemarie R Lang, David K DK Cole, Eric S ES Huseby, Andrew K AK Sewell, Arup K AK Chakraborty, et al.

Indexed on: 07 Oct '14Published on: 07 Oct '14Published in: Cell



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.