8
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

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

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Author and article information

          Journal
          Cell
          Cell
          1097-4172
          0092-8674
          Oct 9 2014
          : 159
          : 2
          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.
          Article
          S0092-8674(14)01158-1 NIHMS654526
          10.1016/j.cell.2014.08.042
          25284152
          06b45b3c-7ade-458c-9913-3b5875ed9822
          Copyright © 2014 Elsevier Inc. All rights reserved.
          History

          Comments

          Comment on this article