The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors
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The csk-associated.pdf
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Author(s)
Davidson, Dominique
Zhong, Ming-Chao
Pandolfi, Pier Paolo
Bolland, Silvia
Seed, Brian
Li, Xin
Gu, Hua
Veillette, André
Xavier, Ramnik Joseph
Date Issued
December 2016
Journal
Cell Reports
Publisher
Elsevier
Citation
Davidson, Dominique, Ming-Chao Zhong, Pier Paolo Pandolfi, Silvia Bolland, Ramnik J. Xavier, Brian Seed, Xin Li, Hua Gu, and André Veillette. “The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors.” Cell Reports 17, no. 10 (December 2016): 2776–2788.
Version
Final published version
Abstract
Summary - 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.
MIT Department
Massachusetts Institute of Technology. Department of Mechanical Engineering
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DOI of Published Version
http://dx.doi.org/10.1016/j.celrep.2016.11.035
