Coreceptor Scanning by the T Cell Receptor Provides a Mechanism for T Cell Tolerance

• Published in: Cell Vol. 159; no. 2; pp. 333 - 345
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.10.2014
• Subjects: Animals; antigens; Autoantigens - immunology; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class II - immunology; Immune Tolerance; Kinetics; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism; Markov Chains; Mice, Inbred C57BL; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; T-lymphocytes; thymocytes; Thymocytes - cytology; Thymocytes - immunology; thymus gland
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2014.08.042

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. [Display omitted] •TCR scans multiple coreceptors to initiate a TCR signal and negative selection•Frequency of Lck loaded coreceptors sets antigen dwell-time threshold•Shorter antigen dwell-time threshold for pMHCII compared to pMHCI self-antigens•“Lck come&stay/signal duration” model explains how the TCR reads antigen dwell time A combination of experimental approaches and mathematic modeling reveals how T cells measure affinity for self-antigens in the thymus to generate self-tolerance.