title: NKG2D triggers cytotoxicity in murine epidermal γδ T cells via PI3K-dependent, Syk/ZAP70-independent signaling pathway.
abstract: Murine epidermal γδ T cells, known as dendritic epidermal T cells (DETCs), survey tissue stress through the invariant T-cell receptor (TCR) and non-clonotypic receptors such as NKG2D. NKG2D signaling via the DAP10-phosphatidylinositol 3-kinase (PI3K) pathway directly stimulates cytotoxicity in natural killer (NK) cells and costimulates CD8(+) T cells to augment TCR signals. In activated murine NK cells, NKG2D signals also via the DAP12-Syk/ZAP70 pathway that triggers both cytotoxicity and cytokine production. It remains controversial whether NKG2D on DETCs is a primary activating receptor or functions only as a costimulatory receptor, and signaling pathways initiated by NKG2D ligation in DETCs have not been analyzed. We show that stimulation of short-term DETC lines with recombinant NKG2D ligands triggers degranulation (exocytosis of cytotoxic granules) via the PI3K-dependent signaling pathway, but does not induce cytokine production or Syk/ZAP70 activation. Coengagement of TCR or Syk/ZAP70 signaling was not crucial for DETC-mediated killing of NKG2D ligand-expressing target cells. Thus, NKG2D can function as a coactivating stress receptor that directly triggers cytotoxicity in DETCs, at least after priming, via the PI3K-dependent, Syk/ZAP70-independent signaling pathway.
authors: Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors: Atsuko
authors: A
authors: Ibusuki
authors: Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Department of Dermatology, Kido Hospital, Niigata, Japan. Electronic address: kazkawai@m2.kufm.kagoshima-u.ac.jp.
authors: Kazuhiro
authors: K
authors: Kawai
authors: Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan; Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors: Shigeru
authors: S
authors: Yoshida
authors: Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors: Youhei
authors: Y
authors: Uchida
authors: Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Ayano
authors: A
authors: Nitahara-Takeuchi
authors: Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors: Kimiko
authors: K
authors: Kuroki
authors: Laboratory for Infectious Immunity, Research Center for Allergy and Immunology (RCAI), RIKEN Yokohama Institute, Yokohama, Japan.
authors: Mizuho
authors: M
authors: Kajikawa
authors: Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors: Toyoyuki
authors: T
authors: Ose
authors: Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors: Katsumi
authors: K
authors: Maenaka
authors: Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors: Masanori
authors: M
authors: Kasahara
authors: Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors: Takuro
authors: T
authors: Kanekura
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002460:Cell Line; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology / Q000378:metabolism; D005089:Exocytosis / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007801:Langerhans Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D000072377:Syk Kinase; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D047908:Intracellular Signaling Peptides and Proteins; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016692:Receptors, Antigen, T-Cell, gamma-delta; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse
references: PLoS One. 2010 Sep 09;5(9):
references: 20844584
references: Immunity. 2002 Jul;17(1):19-29
references: 12150888
references: Immunol Rev. 2010 May;235(1):267-85
references: 20536569
references: Nat Immunol. 2005 Jan;6(1):73-9
references: 15592472
references: Annu Rev Immunol. 2013;31:413-41
references: 23298206
references: J Biol Chem. 1994 Aug 12;269(32):20718-26
references: 8051172
references: Science. 2001 Oct 19;294(5542):605-9
references: 11567106
references: J Immunol. 2004 Mar 15;172(6):3573-9
references: 15004158
references: Science. 1998 Mar 13;279(5357):1729-33
references: 9497293
references: J Immunol. 2011 Jun 15;186(12):6945-54
references: 21562159
references: Cell. 1986 Jun 6;45(5):733-42
references: 3486721
references: J Immunol. 2012 Apr 1;188(7):2972-6
references: 22393149
references: J Immunol. 2005 Feb 15;174(4):1922-31
references: 15699119
references: Science. 1999 Jul 30;285(5428):730-2
references: 10426994
references: Trends Immunol. 2011 Jun;32(6):265-71
references: 21481636
references: Cytometry A. 2008 Sep;73(9):799-807
references: 18548611
references: Nat Immunol. 2003 Jun;4(6):557-64
references: 12740575
references: J Invest Dermatol. 1988 Jul;91(1):62-8
references: 2898506
references: Nat Immunol. 2007 Dec;8(12):1345-52
references: 17952078
references: J Invest Dermatol. 2006 May;126(5):1052-8
references: 16484989
references: Immunology. 2006 Sep;119(1):134-42
references: 16925528
references: Cancer Res. 1993 Sep 1;53(17):4014-9
references: 8358730
references: J Immunol. 2006 Aug 15;177(4):2349-55
references: 16887996
references: Nature. 1998 Feb 12;391(6668):703-7
references: 9490415
references: J Dermatol Sci. 2001 Feb;25(2):150-5
references: 11164711
references: J Immunol. 2004 Aug 15;173(4):2470-8
references: 15294961
references: Nat Rev Immunol. 2003 Oct;3(10):781-90
references: 14523385
references: Nat Immunol. 2002 Dec;3(12):1142-9
references: 12426565
references: Nat Immunol. 2003 Jun;4(6):565-72
references: 12740576
references: J Immunol. 2000 Oct 1;165(7):3695-705
references: 11034374
references: Science. 2011 Dec 2;334(6060):1293-7
references: 22144628
references: Immunity. 2009 Aug 21;31(2):184-96
references: 19699170
references: Br J Dermatol. 2005 Dec;153(6):1101-4
references: 16307643
references: Nat Immunol. 2002 Dec;3(12):1150-5
references: 12426564
references: Int Immunol. 2008 Oct;20(10):1343-9
references: 18697765
references: J Immunol. 2008 Feb 1;180(3):1678-85
references: 18209064
references: J Immunol. 2009 Apr 15;182(8):4557-64
references: 19342629
references: Nat Immunol. 2005 Sep;6(9):928-37
references: 16116470
references: Nat Immunol. 2006 May;7(5):524-32
references: 16582911
references: J Immunol. 2005 Apr 15;174(8):4480-4
references: 15814668
references: Science. 2002 Apr 26;296(5568):747-9
references: 11976459
references: Nat Immunol. 2002 Mar;3(3):288-94
references: 11836527
references: Immunology. 2000 Apr;99(4):489-97
references: 10792495
references: Nat Immunol. 2008 Feb;9(2):146-54
references: 18176566
references: Trends Mol Med. 2008 Apr;14(4):179-89
references: 18353724
references: J Exp Med. 2004 Sep 20;200(6):817-23
references: 15365099
references: J Exp Med. 2002 Apr 1;195(7):855-67
references: 11927630
references: J Immunol. 2001 Nov 15;167(10):5527-30
references: 11698420
references: Nat Rev Immunol. 2010 Jul;10(7):467-78
references: 20539306
references: J Invest Dermatol. 2013 Jun;133(6):1666-9
references: 23334345
references: J Invest Dermatol. 2006 Apr;126(4):808-14
references: 16439970
references: J Immunol. 2002 Apr 1;168(7):3155-64
references: 11907067
references: Immunity. 2012 Aug 24;37(2):314-25
references: 22902232
references: Science. 2010 Sep 3;329(5996):1205-10
references: 20813954
references: Nat Immunol. 2001 Mar;2(3):255-60
references: 11224526
references: J Exp Med. 2012 Dec 17;209(13):2409-22
references: 23166357
references: Eur J Immunol. 2004 Apr;34(4):961-71
references: 15048706
references: Nat Immunol. 2012 Feb 12;13(3):272-82
references: 22327568
references: J Exp Med. 1996 Apr 1;183(4):1483-9
references: 8666906
references: Science. 1991 Jun 7;252(5011):1430-2
references: 1828619
references: J Exp Med. 2000 Oct 2;192(7):1059-68
references: 11015446
references: J Immunol. 2012 Apr 15;188(8):3972-9
references: 22403443