title: PAG/Cbp suppression reveals a contribution of CTLA-4 to setting the activation threshold in T cells.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  We have identified a fail-safe mechanism as well as a novel contribution of CTLA-4 to setting the activation threshold in T cells.
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Strasse 44, Magdeburg, 39120, Germany. jon.lindquist@med.ovgu.de.
authors.forename: Michal
authors.initials: M
authors.lastname: Smida
authors.forename: Clemens
authors.initials: C
authors.lastname: Cammann
authors.forename: Slavyana
authors.initials: S
authors.lastname: Gurbiel
authors.forename: Nadja
authors.initials: N
authors.lastname: Kerstin
authors.forename: Holger
authors.initials: H
authors.lastname: Lingel
authors.forename: Sabine
authors.initials: S
authors.lastname: Lindquist
authors.forename: Luca
authors.initials: L
authors.lastname: Simeoni
authors.forename: Monika C
authors.initials: MC
authors.lastname: Brunner-Weinzierl
authors.forename: Miloslav
authors.initials: M
authors.lastname: Suchanek
authors.forename: Burkhart
authors.initials: B
authors.lastname: Schraven
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Lindquist