Dataset Information

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.

SUBMITTER: Davidson D

PROVIDER: S-EPMC5656005 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors.

Davidson Dominique D Zhong Ming-Chao MC Pandolfi Pier Paolo PP Bolland Silvia S Xavier Ramnik J RJ Seed Brian B Li Xin X Gu Hua H Veillette André A

Cell reports 20161201 10

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 autoimmu ...[more]

PMID: 27926878

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Project description:C-terminal Src kinase (CSK) is a major negative regulator of Src family tyrosine kinases (SFKs) that play critical roles in immunoreceptor signaling. CSK is brought in contiguity to the plasma membrane-bound SFKs via binding to transmembrane adaptor PAG, also known as CSK-binding protein. The recent finding that PAG can function as a positive regulator of the high-affinity IgE receptor (Fc?RI)-mediated mast cell signaling suggested that PAG and CSK have some non-overlapping regulatory functions in mast cell activation. To determine the regulatory roles of CSK in Fc?RI signaling, we derived bone marrow-derived mast cells (BMMCs) with reduced or enhanced expression of CSK from wild-type (WT) or PAG knockout (KO) mice and analyzed their Fc?RI-mediated activation events. We found that in contrast to PAG-KO cells, antigen-activated BMMCs with CSK knockdown (KD) exhibited significantly higher degranulation, calcium response, and tyrosine phosphorylation of Fc?RI, SYK, and phospholipase C. Interestingly, Fc?RI-mediated events in BMMCs with PAG-KO were restored upon CSK silencing. BMMCs with CSK-KD/PAG-KO resembled BMMCs with CSK-KD alone. Unexpectedly, cells with CSK-KD showed reduced kinase activity of LYN and decreased phosphorylation of transcription factor STAT5. This was accompanied by impaired production of proinflammatory cytokines and chemokines in antigen-activated cells. In line with this, BMMCs with CSK-KD exhibited enhanced phosphorylation of protein phosphatase SHP-1, which provides a negative feedback loop for regulating phosphorylation of STAT5 and LYN kinase activity. Furthermore, we found that in WT BMMCs SHP-1 forms complexes containing LYN, CSK, and STAT5. Altogether, our data demonstrate that in Fc?RI-activated mast cells CSK is a negative regulator of degranulation and chemotaxis, but a positive regulator of adhesion to fibronectin and production of proinflammatory cytokines. Some of these pathways are not dependent on the presence of PAG.

Dataset Information

The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors.

Publications

The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors.

Similar Datasets

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