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

Cell. 2014 Oct 9;159(2):333-45. doi: 10.1016/j.cell.2014.08.042. Epub 2014 Oct 2.

Authors

Ondrej Stepanek¹, Arvind S Prabhakar², Celine Osswald³, Carolyn G King³, Anna Bulek⁴, Dieter Naeher³, Marina Beaufils-Hugot³, Michael L Abanto³, Virginie Galati³, Barbara Hausmann³, Rosemarie Lang³, David K Cole⁴, Eric S Huseby⁵, Andrew K Sewell⁴, Arup K Chakraborty⁶, Ed Palmer⁷

Affiliations

¹ Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. Electronic address: ondrej.stepanek@unibas.ch.
² Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
⁴ Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
⁵ Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
⁶ 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.
⁷ Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland. Electronic address: ed.palmer@unibas.ch.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
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
Thymocytes / cytology
Thymocytes / immunology

Substances

Autoantigens
Histocompatibility Antigens Class I
Histocompatibility Antigens Class II
Receptors, Antigen, T-Cell
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)

Abstract

Publication types

MeSH terms

Substances

Grants and funding