title: Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance.
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.
authors.affiliation: Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. Electronic address: ondrej.stepanek@unibas.ch.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Stepanek
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Arvind S
authors.initials: AS
authors.lastname: Prabhakar
authors.affiliation: Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Osswald
authors.affiliation: Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Carolyn G
authors.initials: CG
authors.lastname: King
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Bulek
authors.affiliation: Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Dieter
authors.initials: D
authors.lastname: Naeher
authors.affiliation: Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Marina
authors.initials: M
authors.lastname: Beaufils-Hugot
authors.affiliation: Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Abanto
authors.affiliation: Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Virginie
authors.initials: V
authors.lastname: Galati
authors.affiliation: Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hausmann
authors.affiliation: Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Lang
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Huseby
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science, Departments of Physics, Chemistry, and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, 400 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Arup K
authors.initials: AK
authors.lastname: Chakraborty
authors.affiliation: Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. Electronic address: ed.palmer@unibas.ch.
authors.forename: Ed
authors.initials: E
authors.lastname: Palmer
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance; D007700:Kinetics; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008390:Markov Chains; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000276:immunology
chemical_list: D001324:Autoantigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)