title: NKG2D-dependent activation of dendritic epidermal T cells in contact hypersensitivity.
abstract: The interaction between keratinocytes (KCs) and skin-resident immune cells has an important role in induction of contact hypersensitivity. A specific subset of γδ T cells termed dendritic epidermal T cells (DETCs) are located in mouse epidermis, and we have recently shown that DETCs become activated and produce IL-17 in an IL-1β-dependent manner during contact hypersensitivity. Various receptors on DETCs, including NKG2D, are involved in DETC responses against tumors and during wound healing. The ligands for NKG2D (NKG2DL) are stress-induced proteins such as mouse UL16-binding protein-like transcript 1 (Mult-1), histocompatibility 60 (H60), and retinoic acid early inducible-1 (Rae-1) in mice and major histocompatibility complex (MHC) class I-chain-related A (MICA), MHC class I-chain-related B, and UL16-binding protein in humans. Here, we show that allergens upregulate expression of the NKG2DL Mult-1, H60, and Rae-1 in cultured mouse KCs and of MICA in primary human KCs. We demonstrate that Mult-1 is expressed in mouse skin exposed to allergen. Furthermore, we find that the vast majority of DETCs in murine epidermis and skin-homing cutaneous lymphocyte-associated antigen positive γδ T cells in humans express NKG2D. Finally, we demonstrate that blocking of NKG2D partially inhibits allergen-induced DETC activation. These findings demonstrate that NKG2D and NKG2DL are involved in allergen-induced activation of DETCs and indicate that the NKG2D/NKG2DL pathway might be a potential target for treatment of contact hypersensitivity.
authors: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Skin Inflammation Pharmacology, LEO Pharma A/S, Ballerup, Denmark.
authors: Morten M
authors: MM
authors: Nielsen
authors: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors: Beatrice
authors: B
authors: Dyring-Andersen
authors: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Jonas D
authors: JD
authors: Schmidt
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors: Deborah
authors: D
authors: Witherden
authors: Department of Skin Inflammation Pharmacology, LEO Pharma A/S, Ballerup, Denmark.
authors: Paola
authors: P
authors: Lovato
authors: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Anders
authors: A
authors: Woetmann
authors: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Niels
authors: N
authors: Ødum
authors: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Steen S
authors: SS
authors: Poulsen
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors: Wendy L
authors: WL
authors: Havran
authors: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Carsten
authors: C
authors: Geisler
authors: Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: cmenne@sund.ku.dk.
authors: Charlotte M
authors: CM
authors: Bonefeld
mesh_terms: D000485:Allergens / Q000009:adverse effects; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003877:Dermatitis, Contact / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D007801:Langerhans Cells / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism
chemical_list: D000485:Allergens; D000888:Antibodies, Anti-Idiotypic; D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; C099187:MHC class I-related chain A; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490521:Rae1 protein, mouse; C468260:UL16 binding protein 1, mouse; C114735:minor H antigen H60
references: Nat Rev Immunol. 2012 Jan 13;12(2):114-24
references: 22240625
references: J Invest Dermatol. 2006 May;126(5):1052-8
references: 16484989
references: Contact Dermatitis. 2014 May;70(5):282-90
references: 24460794
references: J Exp Med. 2009 Feb 16;206(2):287-98
references: 19171762
references: Toxicol Appl Pharmacol. 2001 Nov 15;177(1):38-45
references: 11708898
references: Nat Immunol. 2005 Jan;6(1):73-9
references: 15592472
references: Science. 2002 Apr 26;296(5568):747-9
references: 11976459
references: J Immunol. 2012 Apr 15;188(8):3972-9
references: 22403443
references: Cell. 1986 Jun 6;45(5):733-42
references: 3486721
references: J Immunol. 1995 Sep 15;155(6):2888-94
references: 7673705
references: Immunity. 2011 Oct 28;35(4):596-610
references: 21982596
references: PLoS One. 2014 Feb 12;9(2):e86810
references: 24533050
references: Immunity. 2002 Jul;17(1):19-29
references: 12150888
references: J Immunol. 2011 Sep 1;187(5):2783-93
references: 21813772
references: J Immunol. 1993 May 1;150(9):3698-704
references: 8473727
references: Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1398-402
references: 1741395
references: Immunology. 1998 Apr;93(4):469-77
references: 9659217
references: Immunology. 2001 Mar;102(3):323-30
references: 11298831
references: Science. 2011 Dec 2;334(6060):1293-7
references: 22144628
references: Contact Dermatitis. 2013 Jun;68(6):339-47
references: 23692034
references: Eur J Immunol. 2003 Feb;33(2):381-91
references: 12645935
references: J Invest Dermatol. 1989 Feb;92(2):160-5
references: 2918229
references: J Immunol. 1986 Oct 15;137(8):2460-7
references: 2876041
references: J Immunol. 2010 Jan 15;184(2):1102-10
references: 20008290
references: J Immunol. 2009 Apr 15;182(8):4557-64
references: 19342629
references: J Immunol. 1990 Feb 1;144(3):883-91
references: 1967278
references: J Immunol. 2018 Apr 1;200(7):2231-2233
references: 29555676
references: J Invest Dermatol. 2014 Feb;134(2):396-404
references: 23962808
references: J Invest Dermatol. 1990 Jan;94(1):37-42
references: 1688597
references: Allergy. 2009 Dec;64(12):1699-714
references: 19839974
references: Annu Rev Immunol. 2013;31:413-41
references: 23298206
references: Cell Mol Life Sci. 2011 Jul;68(14):2399-408
references: 21560071
references: Immunity. 2000 Jun;12(6):721-7
references: 10894171
references: Adv Exp Med Biol. 1997;417:125-8
references: 9286349
references: J Immunol. 2002 Oct 15;169(8):4079-83
references: 12370332
references: Science. 2001 Oct 19;294(5542):605-9
references: 11567106
references: Nat Immunol. 2008 Feb;9(2):146-54
references: 18176566
references: J Exp Med. 2002 Apr 1;195(7):855-67
references: 11927630
references: J Exp Med. 2009 Apr 13;206(4):743-50
references: 19307328
references: J Immunol. 2004 Mar 15;172(6):3573-9
references: 15004158
references: J Immunol. 1998 Oct 1;161(7):3501-9
references: 9759870
references: J Immunol. 2014 Apr 1;192(7):2975-83
references: 24600030
references: Eur J Immunol. 1997 Jan;27(1):206-14
references: 9022020
references: J Immunol. 2006 Apr 1;176(7):4331-6
references: 16547270
references: Immunity. 2012 Aug 24;37(2):314-25
references: 22902232
references: Science. 2010 Sep 3;329(5996):1205-10
references: 20813954
references: J Exp Med. 2012 Dec 17;209(13):2409-22
references: 23166357