[No authors listed]
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 TÂ 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 TÂ cell activation responses in effector, but not in naive, TÂ cells. PAG-deficient mice also have augmented TÂ cell-dependent autoimmunity and greater resistance to TÂ 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 TÂ cell responses. Unlike PAG, Cbl ubiquitin ligases inhibit the activation of naive, but not of effector, TÂ cells. Thus, Csk-associating PAG is a critical component of the inhibitory machinery controlling effector TÂ cell activation in cooperation with PTPN22 and Dok adaptors.
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