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Reversal of the TCR Stop Signal by CTLA-4

Science, 29 September 2006
Vol. 313, Issue 5795, p. 1972-1975
DOI: 10.1126/science.1131078

Reversal of the TCR Stop Signal by CTLA-4

  1. Helga Schneider1,2,
  2. Jos Downey1,
  3. Andrew Smith3,
  4. Bernd H. Zinselmeyer4,5,
  5. Catherine Rush4,5,
  6. James M. Brewer4,5,
  7. Bin Wei2,
  8. Nancy Hogg3,
  9. Paul Garside4,5,
  10. Christopher E. Rudd1,2,*
  1. 1 Cell Signalling Section, Division of Immunology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
  2. 2 Molecular Immunology Section, Department of Immunology, Division of Investigative Sciences, Imperial College London, London W12 ONN, UK.
  3. 3 Cancer Research UK London Research Institute, Lincoln's Inn Fields, London WC2A 3PX, UK.
  4. 4 Division of Immunology, Infection, and Inflammation, Western Infirmary, University of Glasgow, Glasgow G11 6NT, UK.
  5. 5 Centre for Biophotonics, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK.
  1. * To whom correspondence should be addressed. E-mail: cer51{at}


The coreceptor cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is pivotal in regulating the threshold of signals during T cell activation, although the underlying mechanism is still not fully understood. Using in vitro migration assays and in vivo two-photon laser scanning microscopy, we showed that CTLA-4 increases T cell motility and overrides the T cell receptor (TCR)–induced stop signal required for stable conjugate formation between T cells and antigen-presenting cells. This event led to reduced contact periods between T cells and antigen-presenting cells that in turn decreased cytokine production and proliferation. These results suggest a fundamentally different model of reverse stop signaling, by which CTLA-4 modulates the threshold for T cell activation and protects against autoimmunity.

  • Received for publication 9 June 2006.
  • Accepted for publication 1 August 2006.


H. Schneider, J. Downey, A. Smith, B. H. Zinselmeyer, C. Rush, J. M. Brewer, B. Wei, N. Hogg, P. Garside, and C. E. Rudd, Reversal of the TCR Stop Signal by CTLA-4. Science 313, 1972-1975 (2006).

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