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Science 313 (5795): 1972-1975

Copyright © 2006 by the American Association for the Advancement of Science

Reversal of the TCR Stop Signal by CTLA-4

Helga Schneider,1,2 Jos Downey,1 Andrew Smith,3 Bernd H. Zinselmeyer,4,5 Catherine Rush,4,5 James M. Brewer,4,5 Bin Wei,2 Nancy Hogg,3 Paul Garside,4,5 Christopher E. Rudd1,2*

Abstract: 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.

1 Cell Signalling Section, Division of Immunology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
2 Molecular Immunology Section, Department of Immunology, Division of Investigative Sciences, Imperial College London, London W12 ONN, UK.
3 Cancer Research UK London Research Institute, Lincoln's Inn Fields, London WC2A 3PX, UK.
4 Division of Immunology, Infection, and Inflammation, Western Infirmary, University of Glasgow, Glasgow G11 6NT, UK.
5 Centre for Biophotonics, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK.

* To whom correspondence should be addressed. E-mail: cer51{at}

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