title: PI3Kγ kinase activity is required for optimal T-cell activation and differentiation.
abstract: Phosphatidylinositol-3-kinase gamma (PI3Kγ) is a leukocyte-specific lipid kinase with signaling function downstream of G protein-coupled receptors to regulate cell trafficking, but its role in T cells remains unclear. To investigate the requirement of PI3Kγ kinase activity in T-cell function, we studied T cells from PI3Kγ kinase-dead knock-in (PI3Kγ(KD/KD)) mice expressing the kinase-inactive PI3Kγ protein. We show that CD4(+) and CD8(+) T cells from PI3Kγ(KD/KD) mice exhibit impaired TCR/CD28-mediated activation that could not be rescued by exogenous IL-2. The defects in proliferation and cytokine production were also evident in naïve and memory T cells. Analysis of signaling events in activated PI3Kγ(KD/KD) T cells revealed a reduction in phosphorylation of protein kinase B (AKT) and ERK1/2, a decrease in lipid raft formation, and a delay in cell cycle progression. Furthermore, PI3Kγ(KD/KD) CD4(+) T cells displayed compromised differentiation toward Th1, Th2, Th17, and induced Treg cells. PI3Kγ(KD/KD) mice also exhibited an impaired response to immunization and a reduced delayed-type hypersensitivity to Ag challenge. These findings indicate that PI3Kγ kinase activity is required for optimal T-cell activation and differentiation, as well as for mounting an efficient T cell-mediated immune response. The results suggest that PI3Kγ kinase inhibitors could be beneficial in reducing the undesirable immune response in autoimmune diseases.
authors.affiliation: Janssen Research & Development, LLC, San Diego, CA, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Ladygina
authors.forename: Sridevi
authors.initials: S
authors.lastname: Gottipati
authors.forename: Karen
authors.initials: K
authors.lastname: Ngo
authors.forename: Glenda
authors.initials: G
authors.lastname: Castro
authors.forename: Jing-Ying
authors.initials: JY
authors.lastname: Ma
authors.forename: Homayon
authors.initials: H
authors.lastname: Banie
authors.forename: Tadimeti S
authors.initials: TS
authors.lastname: Rao
authors.forename: Wai-Ping
authors.initials: WP
authors.lastname: Fung-Leung
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D021962:Membrane Microdomains / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D000941:Antigens; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3
keywords: Cell activation; Cell differentiation; Immune responses; PI3K gamma; T cells
references.citation: Nat Rev Mol Cell Biol. 2008 Feb;9(2):99-111
references.pmid: 18216767
references.citation: Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7366-70
references.pmid: 8394019
references.citation: Nat Med. 2005 Sep;11(9):936-43
references.pmid: 16127437
references.citation: Mol Cell Biol. 2000 Aug;20(15):5469-78
references.pmid: 10891487
references.citation: Semin Immunol. 2001 Apr;13(2):115-28
references.pmid: 11308295
references.citation: Science. 1994 Mar 18;263(5153):1609-12
references.pmid: 8128248
references.citation: Curr Top Microbiol Immunol. 2010;346:183-202
references.pmid: 20473789
references.citation: Cell. 2004 Aug 6;118(3):375-87
references.pmid: 15294162
references.citation: Science. 2000 Feb 11;287(5455):1049-53
references.pmid: 10669418
references.citation: J Immunol. 2008 Feb 15;180(4):2081-8
references.pmid: 18250413
references.citation: Cell Rep. 2012 Apr 19;1(4):360-73
references.pmid: 22832227
references.citation: Recent Pat Inflamm Allergy Drug Discov. 2010 Jan;4(1):1-15
references.pmid: 20017720
references.citation: Mol Cell Biol. 1994 May;14(5):3392-402
references.pmid: 8164687
references.citation: FEBS Lett. 2004 Sep 24;575(1-3):35-40
references.pmid: 15388330
references.citation: Science. 1995 Aug 4;269(5224):690-3
references.pmid: 7624799
references.citation: J Exp Med. 2007 Nov 26;204(12):2977-87
references.pmid: 17998387
references.citation: Eur J Immunol. 2012 Oct;42(10):2754-9
references.pmid: 22706993
references.citation: J Immunol. 2012 Nov 1;189(9):4612-20
references.pmid: 23024273
references.citation: Proc Natl Acad Sci U S A. 2007 May 8;104(19):8077-82
references.pmid: 17483449
references.citation: Blood. 2010 Mar 18;115(11):2203-13
references.pmid: 20081091
references.citation: Nat Rev Mol Cell Biol. 2010 May;11(5):329-41
references.pmid: 20379207
references.citation: J Immunol. 2008 Aug 1;181(3):1969-77
references.pmid: 18641334
references.citation: J Allergy Clin Immunol. 2009 Apr;123(4):805-12
references.pmid: 19232703
references.citation: Nat Chem Biol. 2012 Apr 29;8(6):576-82
references.pmid: 22544264
references.citation: J Biol Chem. 2011 Oct 14;286(41):36076-36085
references.pmid: 21862580
references.citation: Nat Immunol. 2002 Nov;3(11):1090-6
references.pmid: 12389041
references.citation: BMC Musculoskelet Disord. 2010 Apr 07;11:63
references.pmid: 20374644
references.citation: Science. 2000 Feb 11;287(5455):1040-6
references.pmid: 10669416
references.citation: Nat Rev Immunol. 2003 Apr;3(4):317-30
references.pmid: 12669022
references.citation: J Immunol. 2006 Jan 1;176(1):589-93
references.pmid: 16365454
references.citation: Nat Immunol. 2002 Nov;3(11):1082-9
references.pmid: 12389042
references.citation: Biochim Biophys Acta. 2008 Jan;1784(1):159-85
references.pmid: 17997386
references.citation: Eur J Immunol. 2011 Mar;41(3):833-44
references.pmid: 21287545
references.citation: Eur J Immunol. 2008 May;38(5):1215-24
references.pmid: 18412166
references.citation: Science. 2002 Aug 9;297(5583):1031-4
references.pmid: 12130661
references.citation: J Exp Med. 2011 Aug 29;208(9):1875-87
references.pmid: 21825017
references.citation: Immunol Lett. 2010 Jun 15;131(1):33-9
references.pmid: 20347874
references.citation: Eur J Immunol. 2012 Dec;42(12):3394-404
references.pmid: 22930133