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Published Online August 24, 2006
Science DOI: 10.1126/science.1131078

Reports

Submitted on June 9, 2006
Accepted on August 1, 2006

Reversal of the TCR Stop Signal by CTLA-4

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

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

* To whom correspondence should be addressed.
Christopher E. Rudd , E-mail: cer51{at}cam.ac.uk

The co-receptor CTLA-4 is pivotal in regulating the threshold of signals during T-cell activation, although the mechanism is still not fully understood. Using in vitro migration assays and in vivo by two-photon microscopy, we show that CTLA-4 increases T-cell motility and over-rides the 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 APCs 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.


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