The aryl hydrocarbon receptor is required for the maintenance of liver-resident natural killer cells.
A tissue-resident population of natural killer cells (NK cells) in the liver has recently been described to have the unique capacity to confer immunological memory in the form of hapten-specific contact hypersensitivity independent of T and B cells. Factors regulating the development and maintenance of these liver-resident NK cells are poorly understood. The aryl hydrocarbon receptor (AhR) is a transcription factor modulated by exogenous and endogenous ligands that is important in the homeostasis of immune cells at barrier sites, such as the skin and gut. In this study, we show that liver-resident NK (NK1.1+CD3-) cells, defined as CD49a+TRAIL+CXCR6+DX5-cells in the mouse liver, constitutively express AhR. In AhR-/-mice, there is a significant reduction in the proportion and absolute number of these cells, which results from a cell-intrinsic dependence on AhR. This deficiency in liver-resident NK cells appears to be the result of higher turnover and increased susceptibility to cytokine-induced cell death. Finally, we show that this deficiency has functional implications in vivo. Upon hapten exposure, AhR-/-mice are not able to mount an NK cell memory response to hapten rechallenge. Together, these data demonstrate the requirement of AhR for the maintenance of CD49a+TRAIL+CXCR6+DX5-liver-resident NK cells and their hapten memory function.
Division of Head and Neck Surgery, Department of Otolaryngology, Program in Immunology, Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Luhua H
0000-0003-3870-0574
LH
Zhang
Division of Head and Neck Surgery, Department of Otolaryngology, Program in Immunology, Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
June Ho
0000-0001-9278-1331
JH
Shin
Division of Head and Neck Surgery, Department of Otolaryngology, Program in Immunology, Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Mikel D
0000-0002-7001-9132
MD
Haggadone
Division of Head and Neck Surgery, Department of Otolaryngology, Program in Immunology, Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305 sunwoo@stanford.edu.
John B
0000-0002-8393-4196
JB
Sunwoo
D000818:Animals; D003877:Dermatitis, Contact / Q000276:immunology / Q000473:pathology; D006706:Homeostasis; D039423:Integrin alpha1 / Q000378:metabolism; D039421:Integrin alpha2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism*; D008099:Liver / Q000166:cytology*; D008810:Mice, Inbred C57BL; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
D039423:Integrin alpha1; D039421:Integrin alpha2; D018336:Receptors, Aryl Hydrocarbon; D053221:TNF-Related Apoptosis-Inducing Ligand
Nat Immunol. 2010 Dec;11(12):1127-35
20972432
Nat Immunol. 2006 May;7(5):507-16
16617337
Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1915-9
19181844
Immunity. 2012 Jan 27;36(1):92-104
22177117
J Clin Invest. 2013 Apr;123(4):1444-56
23524967
Cell. 2011 Oct 28;147(3):629-40
21999944
Immunity. 2014 Dec 18;41(6):988-1000
25500367
Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12391-6
23836658
Nat Immunol. 2011 Nov 20;13(2):144-51
22101730
Front Immunol. 2014 Jun 16;5:282
24982658
Immunity. 2012 Jan 27;36(1):55-67
22261438
J Clin Invest. 2014 Nov;124(11):5037-41
25295539
Cell Rep. 2014 Jul 10;8(1):150-62
24953655
Elife. 2014 Jan 01;3:e01659
24714492
Science. 2011 Dec 16;334(6062):1561-5
22033518
Cell Mol Immunol. 2013 May;10(3):196-201
23563088
Front Immunol. 2012 Feb 06;3:10
22566896
PLoS Pathog. 2011 Aug;7(8):e1002141
21829360
Lancet. 2015 Feb 26;385 Suppl 1:S45
26312867
Blood. 2005 Mar 1;105(5):2082-9
15536146
Nat Rev Immunol. 2013 Feb;13(2):145-9
23348417
J Exp Med. 2014 Mar 10;211(3):563-77
24516120
J Immunol. 2015 Mar 15;194(6):2467-71
25672754
Nature. 2009 Jan 29;457(7229):557-61
19136945