Journal
CELL CYCLE
Volume 15, Issue 8, Pages 1073-1083Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2016.1156267
Keywords
Conditional knockout; G1-S arrest; metabolism; phosphatase; T cell proliferation
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Funding
- NHRI, Taiwan [03-A1-IMPP03-014]
- Ministry of Science and Technology, Taiwan [101-2320-B-400-004-MY3/103-2321-B-400-004]
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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 AMPK1 retarded the proliferation of WT T cells. Further investigations showed that PP4 co-immunoprecipitated with AMPK1, 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.
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