title: T cell proliferation and adaptive immune responses are critically regulated by protein phosphatase 4.
abstract: The clonal expansion of activated T cells is pivotal for the induction of protective immunity. Protein phosphatase 4 (PP4) is a ubiquitously expressed serine/threonine phosphatase with reported functions in thymocyte development and DNA damage responses. However, the role of PP4 in T cell immunity has not been thoroughly investigated. In this report, our data showed that T cell-specific ablation of PP4 resulted in defective adaptive immunity, impaired T cell homeostatic expansion, and inefficient T cell proliferation. This hypo-proliferation was associated with a partial G1-S cell cycle arrest, enhanced transcriptions of CDK inhibitors and elevated activation of AMPK. In addition, resveratrol, a known AMPK activator, induced similar G1-S arrests, while lentivirally-transduced WT or constitutively-active AMPKα1 retarded the proliferation of WT T cells. Further investigations showed that PP4 co-immunoprecipitated with AMPKα1, and the over-expression of PP4 inhibited AMPK phosphorylation, thereby implicating PP4 for the negative regulation of AMPK. In summary, our results indicate that PP4 is an essential modulator for T cell proliferation and immune responses; they further suggest a potential link between PP4 functions, AMPK activation and G1-S arrest in activated T cells.
authors.affiliation: a Immunology Research Center, National Health Research Institutes , Zhunan , Miaoli County , Taiwan.
authors.forename: Fang-Hsuean
authors.initials: FH
authors.lastname: Liao
authors.affiliation: a Immunology Research Center, National Health Research Institutes , Zhunan , Miaoli County , Taiwan.
authors.forename: Wan-Yi
authors.initials: WY
authors.lastname: Hsiao
authors.affiliation: a Immunology Research Center, National Health Research Institutes , Zhunan , Miaoli County , Taiwan.
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lin
authors.affiliation: a Immunology Research Center, National Health Research Institutes , Zhunan , Miaoli County , Taiwan.
authors.forename: Yi-Chiao
authors.initials: YC
authors.lastname: Chan
authors.affiliation: a Immunology Research Center, National Health Research Institutes , Zhunan , Miaoli County , Taiwan.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Huang
mesh_terms: D056704:Adaptive Immunity; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004789:Enzyme Activation; D017353:Gene Deletion; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D056724:Immunity, Humoral; D019426:Integrases / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007376:Interleukin-2; D000263:Adenylate Kinase; C045073:Cre recombinase; D019426:Integrases; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4
keywords: Conditional knockout; G1-S arrest; T cell proliferation; metabolism; phosphatase