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Helga Schneider,1,2Jos Downey,1Andrew Smith,3Bernd H. Zinselmeyer,4,5Catherine Rush,4,5James M. Brewer,4,5Bin Wei,2Nancy Hogg,3Paul Garside,4,5Christopher E. Rudd1,2*
The coreceptor cytotoxic T lymphocyte–associated antigen4 (CTLA-4) is pivotal in regulating the threshold of signalsduring T cell activation, although the underlying mechanismis still not fully understood. Using in vitro migration assaysand in vivo two-photon laser scanning microscopy, we showedthat CTLA-4 increases T cell motility and overrides the T cellreceptor (TCR)–induced stop signal required for stableconjugate formation between T cells and antigen-presenting cells.This event led to reduced contact periods between T cells andantigen-presenting cells that in turn decreased cytokine productionand proliferation. These results suggest a fundamentally differentmodel of reverse stop signaling, by which CTLA-4 modulates thethreshold 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}cam.ac.uk
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