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Although protein phosphatase 2A (PP2A) is required for T\u2010cell development and function, the role of PPP2CB, which is the catalytic subunit \u03b2 isoform of PP2A, remains unknown. In the present study, using a T cell\u2010specific knockout mouse of PPP2CB (PPP2CB<jats:sup>fl\/fl<\/jats:sup> Lck\u2010Cre<jats:sup>+<\/jats:sup>), we demonstrated that PPP2CB was dispensable for T\u2010cell development in the thymus and peripheral lymphoid organs. Furthermore, PPP2CB deletion did not affect T\u2010cell receptor (TCR)\u2010induced T\u2010cell activation or cytokine\u2010induced T\u2010cell responses; however, it specifically enhanced phorbol myristate acetate (PMA) plus ionomycin\u2010induced T\u2010cell activation with increased cellular proliferation, elevated CD69 and CD25 expression, and enhanced cytokine production (inteferon\u2010\u03b3, interleukin\u20102 and tumor necrosis factor). Mechanistic analyses suggested that the PPP2CB deletion enhanced activation of the phosphoinositide 3\u2010kinase\/Akt signaling pathway and Ca<jats:sup>2+<\/jats:sup> flux following stimulation with PMA plus ionomycin. Moreover, the specific PI3K inhibitor rescued the augmented cell activation in PPP2CB\u2010deficient T cells. Using mass spectrometry\u2010based phospho\u2010peptide analysis, we identified potential substrates of PPP2CB during PMA plus ionomycin\u2010induced T\u2010cell activation. Collectively, our study provides evidence of the specific role of PPP2CB in controlling PMA plus ionomycin\u2010induced T\u2010cell activation.<\/jats:p>","DOI":"10.1111\/febs.16370","type":"journal-article","created":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T09:10:28Z","timestamp":1643015428000},"page":"4518-4535","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Protein phosphatase 2A catalytic subunit \u03b2 suppresses PMA\/ionomycin\u2010induced T\u2010cell activation by negatively regulating PI3K\/Akt signaling"],"prefix":"10.1111","volume":"289","author":[{"given":"Rui","family":"Gao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Proteomics Beijing Proteome Research Center National Center for Protein Sciences (Beijing) Beijing Institute of Lifeomics  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