title: The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors.
abstract: The transmembrane adaptor PAG (Cbp) has been proposed to mediate membrane recruitment of Csk, a cytoplasmic protein tyrosine kinase playing a critical inhibitory role during T cell activation, by inactivating membrane-associated Src kinases. However, this model has not been validated by genetic evidence. Here, we demonstrate that PAG-deficient mice display enhanced T cell activation responses in effector, but not in naive, T cells. PAG-deficient mice also have augmented T cell-dependent autoimmunity and greater resistance to T cell anergy. Interestingly, in the absence of PAG, Csk becomes more associated with alternative partners; i.e., phosphatase PTPN22 and Dok adaptors. Combining PAG deficiency with PTPN22 or Dok adaptor deficiency further enhances effector T cell responses. Unlike PAG, Cbl ubiquitin ligases inhibit the activation of naive, but not of effector, T cells. Thus, Csk-associating PAG is a critical component of the inhibitory machinery controlling effector T cell activation in cooperation with PTPN22 and Dok adaptors.
authors.affiliation: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC H2W 1R7, Canada. Electronic address: dominique.davidson@ircm.qc.ca.
authors.forename: Dominique
authors.initials: D
authors.lastname: Davidson
authors.affiliation: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC H2W 1R7, Canada.
authors.forename: Ming-Chao
authors.initials: MC
authors.lastname: Zhong
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA 02215, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bolland
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Seed
authors.affiliation: Laboratory of Molecular Immunology, Institut de recherches cliniques de Montréal, Montréal, QC H2W 1R7, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Immunology, Institut de recherches cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Department of Medicine, University of Montréal, Montréal, QC H3C 3J7, Canada; Department of Medicine, McGill University, Montréal, QC H3G 1Y6, Canada.
authors.forename: Hua
authors.initials: H
authors.lastname: Gu
authors.affiliation: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Department of Medicine, University of Montréal, Montréal, QC H3C 3J7, Canada; Department of Medicine, McGill University, Montréal, QC H3G 1Y6, Canada. Electronic address: veillea@ircm.qc.ca.
authors.forename: André
authors.initials: A
authors.lastname: Veillette
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C408344:Pag protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D011948:Receptors, Antigen, T-Cell; D050721:Proto-Oncogene Proteins c-cbl; D019061:src-Family Kinases; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse; C493849:Cbl protein, mouse
keywords: Cbl; Cbp; Csk kinase; Dok; PAG; PTPN22; Src kinases; T cell activation; TCR signaling; adaptor