ArticleCell & bioscience2014
Protein phosphatase 4 is an essential positive regulator for Treg development, function, and protective gut immunity.
Article in Cell & bioscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 23 citations in OpenAlex.
- Acly Deficiency Enhances Myelopoiesis through Acetyl Coenzyme A and Metabolic-Epigenetic Cross-Talk.ImmunoHorizons · 2022Article
- Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy.Signal transduction and targeted therapy · 2022Review
- Regulation of TLR4 signaling through the TRAF6/sNASP axis by reversible phosphorylation mediated by CK2 and PP4.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Smek1 deficiency exacerbates experimental autoimmune encephalomyelitis by activating proinflammatory microglia and suppressing the IDO1-AhR pathway.Journal of neuroinflammation · 2021Article
- A Systems Biology Workflow for Drug and Vaccine Repurposing: Identifying Small-Molecule BCG Mimics to Reduce or Prevent COVID-19 Mortality.Pharmaceutical research · 2020Article
- DAF-16 and SMK-1 Contribute to Innate Immunity During Adulthood inG3 (Bethesda, Md.) · 2020Article
- Functional roles of protein phosphatase 4 in multiple aspects of cellular physiology: a friend and a foe.BMB reports · 2020Review
- Photoactivatable RNAi for cancer gene therapy triggered by near-infrared-irradiated single-walled carbon nanotubes.International journal of nanomedicine · 2017Article
- Protein phosphatase 4 catalytic subunit is overexpressed in glioma and promotes glioma cell proliferation and invasion.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- T cell proliferation and adaptive immune responses are critically regulated by protein phosphatase 4.Cell cycle (Georgetown, Tex.) · 2016Article
- Genetically engineered mouse models for studying inflammatory bowel disease.The Journal of pathology · 2016Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundProtein phosphates 4 (PP4), encoded by the ppp4c gene, is a ubiquitously expressed phosphatase that has been implicated in the regulation of cytokine signaling and lymphocyte survival; recent reports suggest that PP4 may be involved in pre-TCR signaling and B cell development. However, whether PP4 also modulates the functions of peripheral T cells has not been investigated due to the lack of a suitable in vivo model. Treg cells are a specialized subset of CD4 helper T cells that can suppress the proliferation of activated effector T cells. In the absence of this negative regulation, autoimmune syndromes and inflammatory diseases, such as human Crohn's disease, will arise.
resultsIn this report, we generated mice with T cell-specific ablation of the ppp4c gene (CD4cre:PP4(f/f)) and a Foxp3-GFP reporter gene to examine the roles of PP4 in Treg development and function. Characterizations of the CD4cre:PP4(f/f) mice showed that PP4 deficiency induced partial αβ T lymphopenia and T cell hypo-proliferation. Further analyses revealed significant reductions in the numbers of thymic and peripheral Treg cells, as well as in the efficiency of in vitro Treg polarization. In addition, PP4-deficient Treg cells exhibited reduced suppressor functions that were associated with decreased IL-10, CTLA4, GITR and CD103 expression. More interestingly, the CD4cre:PP4(f/f) mice developed spontaneous rectal prolapse and colitis with symptoms similar to human Crohn's disease. The pathogenesis of colitis required the presence of commensal bacteria, and was correlated with reduced Treg cells in the gut. Nevertheless, PP4-deficient Treg cells were still capable of suppressing experimental colitis, suggesting that multiple factors contributed to the onset of the spontaneous colitis.
conclusionsWhile the molecular mechanisms remain to be investigated, our results clearly show that PP4 plays a non-redundant role for the differentiation, suppressor activity and gut homeostasis of Treg cells. The onset of spontaneous colitis in the CD4cre:PP4(f/f) mice further suggests that PP4 is essential for the maintenance of protective gut immunity. The CD4cre:PP4(f/f) mice thus may serve as a good model for studying the interactions between Treg cells and gut commensal bacteria for the regulation of mucosal immunity.
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Registered trials
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