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PAG/Cbp suppression reveals a contribution of CTLA-4 to setting the activation threshold in T cells

Michal Smida12, Clemens Cammann1, Slavyana Gurbiel1, Nadja Kerstin1, Holger Lingel3, Sabine Lindquist45, Luca Simeoni1, Monika C Brunner-Weinzierl3, Miloslav Suchanek6, Burkhart Schraven17 and Jonathan A Lindquist18*

Author Affiliations

1 Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Strasse 44, Magdeburg, 39120, Germany

2 Current address: Center for Molecular Medicine, Lazarettgasse 14, AKH BT 25.3, Vienna, 1090, Austria

3 Department of Experimental Pediatrics, Otto-von-Guericke University, Leipziger Strasse 44, Magdeburg, 39120, Germany

4 Department of Neurology, Hannover Medical School, Carl-Neuberg-Str.1, Hannover, 30625, Germany

5 Department of Neurochemistry and Molecular Biology, Leibniz-Institute for Neurobiology, Brenneckestr. 6, Magdeburg, 39118, Germany

6 EXBIO Praha, a.s., Nad Safinou II 341, Vestec, 252 42, Czech Republic

7 Department of Immune Control, Helmholtz Centre for Infection Research, Braunschweig, Germany

8 Current address: Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, Magdeburg, 39120, Germany

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Cell Communication and Signaling 2013, 11:28  doi:10.1186/1478-811X-11-28

Published: 19 April 2013



PAG/Cbp represents a ubiquitous mechanism for regulating Src family kinases by recruiting Csk to the plasma membrane, thereby controlling cellular activation. Since Src kinases are known oncogenes, we used RNA interference in primary human T cells to test whether the loss of PAG resulted in lymphocyte transformation.


PAG-depletion enhanced Src kinase activity and augmented proximal T-cell receptor signaling; exactly the phenotype expected for loss of this negative regulator. Surprisingly, rather than becoming hyper-proliferative, PAG-suppressed T cells became unresponsive. This was mediated by a Fyn-dependent hyper-phosphorylation of the inhibitory receptor CTLA-4, which recruited the protein tyrosine phosphatase Shp-1 to lipid rafts. Co-suppression of CTLA-4 abrogates this inhibition and restores proliferation to T cells.


We have identified a fail-safe mechanism as well as a novel contribution of CTLA-4 to setting the activation threshold in T cells.

Human; T cells; Protein kinases; Cell activation; Tolerance