title: Loss of Functionally Redundant p38 Isoforms in T Cells Enhances Regulatory T Cell Induction.
abstract: The evolutionarily conserved protein kinase p38 mediates innate resistance to environmental stress and microbial infection. Four p38 isoforms exist in mammals and may have been co-opted for new roles in adaptive immunity. Murine T cells deficient in p38α, the ubiquitously expressed p38 isoform, showed no readily apparent cell-autonomous defects while expressing elevated amounts of another isoform, p38β. Mice with T cells simultaneously lacking p38α and p38β displayed lymphoid atrophy and elevated Foxp3+regulatory T cell frequencies. Double deficiency of p38α and p38β in naïve CD4+T cells resulted in an attenuation of MAPK-activated protein kinase (MK)-dependent mTOR signaling after T cell receptor engagement, and enhanced their differentiation into regulatory T cells under appropriate inducing conditions. Pharmacological inhibition of the p38-MK-mTOR signaling module produced similar effects, revealing potential for therapeutic applications.
authors.affiliation: From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129; the Department of Biochemistry, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Morisada
authors.initials: M
authors.lastname: Hayakawa
authors.affiliation: From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129; the Department of Biochemistry, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hayakawa
authors.affiliation: the Division of Cell Signalling and Immunology, School of Life Sciences, Wellcome Trust Building, Dundee DD1 5EH, United Kingdom.
authors.forename: Tsvetana
authors.initials: T
authors.lastname: Petrova
authors.affiliation: From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129; the Department of Microbiology and Immunology and Research Unit of Oral Microbiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Patcharee
authors.initials: P
authors.lastname: Ritprajak
authors.affiliation: the Division of Cell Signalling and Immunology, School of Life Sciences, Wellcome Trust Building, Dundee DD1 5EH, United Kingdom.
authors.forename: Ruhcha V
authors.initials: RV
authors.lastname: Sutavani
authors.affiliation: From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Guillermina Yanek
authors.initials: GY
authors.lastname: Jiménez-Andrade
authors.affiliation: From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Sano
authors.affiliation: From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Choo
authors.affiliation: From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: John
authors.initials: J
authors.lastname: Seavitt
authors.affiliation: MRC Protein Phosphorylation Unit, School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors.forename: Ram K C
authors.initials: RKC
authors.lastname: Venigalla
authors.affiliation: the Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom.
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.affiliation: From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Katia
authors.initials: K
authors.lastname: Georgopoulos
authors.affiliation: the Division of Cell Signalling and Immunology, School of Life Sciences, Wellcome Trust Building, Dundee DD1 5EH, United Kingdom.
authors.forename: J Simon C
authors.initials: JSC
authors.lastname: Arthur
authors.affiliation: From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129. Electronic address: jmpark@cbrc2.mgh.harvard.edu.
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Park
mesh_terms: D000818:Animals; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D048290:Mitogen-Activated Protein Kinase 11 / Q000235:genetics / Q000276:immunology*; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14
keywords: T-cell; immunology; mouse; p38; signal transduction