The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors
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 ge...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2017
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| Online Access: | http://hdl.handle.net/1721.1/107815 |
| _version_ | 1826190900460519424 |
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| author | Davidson, Dominique Zhong, Ming-Chao Pandolfi, Pier Paolo Bolland, Silvia Seed, Brian Li, Xin Gu, Hua Veillette, André Xavier, Ramnik Joseph |
| author2 | Massachusetts Institute of Technology. Department of Mechanical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Mechanical Engineering Davidson, Dominique Zhong, Ming-Chao Pandolfi, Pier Paolo Bolland, Silvia Seed, Brian Li, Xin Gu, Hua Veillette, André Xavier, Ramnik Joseph |
| author_sort | Davidson, Dominique |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:47:21Z |
| format | Article |
| id | mit-1721.1/107815 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:47:21Z |
| publishDate | 2017 |
| publisher | Elsevier |
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| spelling | mit-1721.1/1078152022-09-23T14:33:47Z The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors Davidson, Dominique Zhong, Ming-Chao Pandolfi, Pier Paolo Bolland, Silvia Seed, Brian Li, Xin Gu, Hua Veillette, André Xavier, Ramnik Joseph Massachusetts Institute of Technology. Department of Mechanical Engineering Xavier, Ramnik Joseph 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. Canadian Institutes of Health Research (FRN #143338) 2017-04-03T14:03:35Z 2017-04-03T14:03:35Z 2016-12 2016-10 Article http://purl.org/eprint/type/JournalArticle 22111247 http://hdl.handle.net/1721.1/107815 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. en_US http://dx.doi.org/10.1016/j.celrep.2016.11.035 Cell Reports Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Elsevier |
| spellingShingle | Davidson, Dominique Zhong, Ming-Chao Pandolfi, Pier Paolo Bolland, Silvia Seed, Brian Li, Xin Gu, Hua Veillette, André Xavier, Ramnik Joseph The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors |
| title | The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors |
| title_full | The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors |
| title_fullStr | The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors |
| title_full_unstemmed | The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors |
| title_short | The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors |
| title_sort | csk associated adaptor pag inhibits effector t cell activation in cooperation with phosphatase ptpn22 and dok adaptors |
| url | http://hdl.handle.net/1721.1/107815 |
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