title: Pim-2 Kinase Influences Regulatory T Cell Function and Stability by Mediating Foxp3 Protein N-terminal Phosphorylation.
abstract: Regulation of the extent of immune responses is a requirement to maintain self-tolerance and limit inflammatory processes. CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells play a role in regulation. The Foxp3 transcription factor is considered a dominant regulator for Treg cell development and function. Foxp3 function itself is directly regulated by multiple posttranslational modifications that occur in response to various external stimuli. The Foxp3 protein is a component of several dynamic macromolecular regulatory complexes. The complexes change constituents over time and through different signals to regulate the development and function of regulatory T cells. Here we identified a mechanism regulating Foxp3 level and activity that operates through discrete phosphorylation. The Pim-2 kinase can phosphorylate Foxp3, leading to decreased suppressive functions of Treg cells. The amino-terminal domain of Foxp3 is modified at several sites by Pim-2 kinase. This modification leads to altered expression of proteins related to Treg cell functions and increased Treg cell lineage stability. Treg cell suppressive function can be up-regulated by either pharmacologically inhibiting Pim-2 kinase activity or by genetically knocking out Pim-2 in rodent Treg cells. Deficiency of Pim-2 activity increases murine host resistance to dextran sodium sulfate-induced colitis in vivo, and a Pim-2 small molecule kinase inhibitor also modified Treg cell functions. Our studies define a pathway for limiting the regulation of Foxp3 function because the Pim-2 kinase represents a potential therapeutic target for modulating the Treg cell suppressive activities in controlling immune responses.
authors.affiliation: From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Guoping
authors.initials: G
authors.lastname: Deng
authors.affiliation: From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: the Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: the Barnett Institute of Chemical and Biological Analysis, Department of Chemistry and Chemical Biology, College of Science, Northeastern University, Boston, Massachusetts 02115-5000.
authors.forename: Shujia
authors.initials: S
authors.lastname: Dai
authors.affiliation: From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Takuya
authors.initials: T
authors.lastname: Ohtani
authors.affiliation: the Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom, and.
authors.forename: Alison
authors.initials: A
authors.lastname: Banham
authors.affiliation: the Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: the Barnett Institute of Chemical and Biological Analysis, Department of Chemistry and Chemical Biology, College of Science, Northeastern University, Boston, Massachusetts 02115-5000.
authors.forename: Shiaw-Lin
authors.initials: SL
authors.lastname: Wu
authors.affiliation: the Division of Transplant Immunology and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Wayne
authors.initials: W
authors.lastname: Hancock
authors.affiliation: From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Arabinda
authors.initials: A
authors.lastname: Samanta
authors.affiliation: From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, greene@reo.med.upenn.edu.
authors.forename: Mark I
authors.initials: MI
authors.lastname: Greene
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C094167:Pim2 protein, mouse; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases
keywords: Foxp3; Pim2 kinase; autoimmunity; colitis; immunosuppression; phosphorylation; posttranslational modification (PTM); regulatory T cell