Initiation of T cell signaling by CD45 segregation at 'close contacts'

Research output: Contribution to journalArticle

Abstract

It has been proposed that the local segregation of kinases and the tyrosine phosphatase CD45 underpins T cell antigen receptor (TCR) triggering, but how such segregation occurs and whether it can initiate signaling is unclear. Using structural and biophysical analysis, we show that the extracellular region of CD45 is rigid and extends beyond the distance spanned by TCR-ligand complexes, implying that sites of TCR-ligand engagement would sterically exclude CD45. We also show that the formation of 'close contacts', new structures characterized by spontaneous CD45 and kinase segregation at the submicron-scale, initiates signaling even when TCR ligands are absent. Our work reveals the structural basis for, and the potent signaling effects of, local CD45 and kinase segregation. TCR ligands have the potential to heighten signaling simply by holding receptors in close contacts.

Details

Authors
  • Veronica T Chang
  • Ricardo A Fernandes
  • Kristina A Ganzinger
  • Steven F Lee
  • Christian Siebold
  • James McColl
  • Peter Jönsson
  • Matthieu Palayret
  • Karl Harlos
  • Charlotte H Coles
  • E Yvonne Jones
  • Yuan Lui
  • Elizabeth Huang
  • Robert J C Gilbert
  • David Klenerman
  • A Radu Aricescu
  • Simon J Davis
External organisations
  • University of Oxford
  • University of Cambridge
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology

Keywords

  • Crystallography, X-Ray, HEK293 Cells, Humans, Jurkat Cells, Leukocyte Common Antigens, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Microscopy, Electron, Microscopy, Fluorescence, Models, Molecular, Protein Structure, Tertiary, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Time Factors, ZAP-70 Protein-Tyrosine Kinase, Journal Article, Research Support, Non-U.S. Gov't
Original languageEnglish
Pages (from-to)574-582
Number of pages9
JournalNature Immunology
Volume17
Issue number5
Publication statusPublished - 2016 May
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes

Total downloads

No data available

Related projects

Peter Jönsson

2015/01/012018/12/31

Project: ResearchIndividual research project

View all (1)