Protein phosphatase 2A catalytic subunit β suppresses PMA/ionomycin‐induced T‐cell activation by negatively regulating PI3K/Akt signaling
Rui Gao, Xin Li, Huiying Gao, Ke Zhao, Xian Liu, Jinfang Liu, Qi Wang, Yaxin Zhu, Hui Chen, Shensi Xiang, Yi‐Qun Zhan, Ronghua Yin, Miao Yu, Hongmei Ning, Xiaoming Yang, Chang‐Yan Li
Abstract
The precise regulation of the T‐cell activation process is critical for overall immune homeostasis. Although protein phosphatase 2A (PP2A) is required for T‐cell development and function, the role of PPP2CB, which is the catalytic subunit β isoform of PP2A, remains unknown. In the present study, using a T cell‐specific knockout mouse of PPP2CB (PPP2CB fl/fl Lck‐Cre + ), we demonstrated that PPP2CB was dispensable for T‐cell development in the thymus and peripheral lymphoid organs. Furthermore, PPP2CB deletion did not affect T‐cell receptor (TCR)‐induced T‐cell activation or cytokine‐induced T‐cell responses; however, it specifically enhanced phorbol myristate acetate (PMA) plus ionomycin‐induced T‐cell activation with increased cellular proliferation, elevated CD69 and CD25 expression, and enhanced cytokine production (inteferon‐γ, interleukin‐2 and tumor necrosis factor). Mechanistic analyses suggested that the PPP2CB deletion enhanced activation of the phosphoinositide 3‐kinase/Akt signaling pathway and Ca 2+ flux following stimulation with PMA plus ionomycin. Moreover, the specific PI3K inhibitor rescued the augmented cell activation in PPP2CB‐deficient T cells. Using mass spectrometry‐based phospho‐peptide analysis, we identified potential substrates of PPP2CB during PMA plus ionomycin‐induced T‐cell activation. Collectively, our study provides evidence of the specific role of PPP2CB in controlling PMA plus ionomycin‐induced T‐cell activation.