title: Natural killer cell biology: an update and future directions.
abstract: Natural killer (NK) cells constitute a minor subset of normal lymphocytes that initiate innate immune responses toward tumor and virus-infected cells. They can mediate spontaneous cytotoxicity toward these abnormal cells and rapidly secrete numerous cytokines and chemokines to promote subsequent adaptive immune responses. Significant progress has been made in the past 2 decades to improve our understanding of NK cell biology. Here we review recent discoveries, including a better comprehension of the "education" of NK cells to achieve functional competence during their maturation and the discovery of "memory" responses by NK cells, suggesting that they might also contribute to adaptive immunity. The improved understanding of NK cell biology has forged greater awareness that these cells play integral early roles in immune responses. In addition, several promising clinical therapies have been used to exploit NK cell functions in treating patients with cancer. As our molecular understanding improves, these and future immunotherapies should continue to provide promising strategies to exploit the unique functions of NK cells to treat cancer, infections, and other pathologic conditions.
authors.affiliation: Immune Cell Development and Host Defense Program, the Research Institute at Fox Chase Cancer Center, Philadelphia, Pa. Electronic address: kerry.campbell@fccc.edu.
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Campbell
authors.affiliation: Immune Cell Development and Host Defense Program, the Research Institute at Fox Chase Cancer Center, Philadelphia, Pa.
authors.forename: Jun
authors.initials: J
authors.lastname: Hasegawa
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology*; D055607:Receptors, Natural Killer Cell / Q000276:immunology
chemical_list: D055607:Receptors, Natural Killer Cell
keywords: ADCC; AML; Acute myeloid leukemia; Antibody-dependent cellular cytotoxicity; CAR; Chimeric antigen receptor; Class I MHC; HSC; Hematopoietic stem cell; IFN-γ; ILC; ITIM; Immunoreceptor tyrosine-based inhibitory motif; Innate lymphoid cell; KIR; Killer cell immunoglobulin-like receptor; MCMV; MHC-I; MM; Mouse cytomegalovirus; Multiple myeloma; NCR; NK; Natural cytotoxicity receptor; Natural killer; Natural killer cell; PD-1; Programmed cell death 1; SRIR; Self-recognizing inhibitory receptor; antibody-dependent cellular cytotoxicity; cancer; hematopoietic stem cell transplantation; immune memory; immunomodulatory drugs; innate immunity; killer cell immunoglobulin-like receptors; viral infection
references.citation: Trends Immunol. 2009 Apr;30(4):143-9
references.pmid: 19282243
references.citation: J Exp Med. 2011 Jan 17;208(1):13-21
references.pmid: 21173105
references.citation: Nat Immunol. 2008 May;9(5):495-502
references.pmid: 18425106
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):728-32
references.pmid: 21187373
references.citation: Annu Rev Immunol. 2002;20:217-51
references.pmid: 11861603
references.citation: J Exp Med. 2010 Oct 25;207(11):2369-81
references.pmid: 20876312
references.citation: Immunity. 2004 Jul;21(1):55-66
references.pmid: 15345220
references.citation: Immunity. 1997 Dec;7(6):739-51
references.pmid: 9430220
references.citation: J Exp Med. 2012 May 7;209(5):947-54
references.pmid: 22493516
references.citation: J Innate Immun. 2011;3(3):258-63
references.pmid: 21411969
references.citation: Blood. 2011 Jan 20;117(3):1021-9
references.pmid: 21045194
references.citation: Nat Genet. 2002 Aug;31(4):429-34
references.pmid: 12134147
references.citation: Nature. 2011 Nov 20;481(7381):394-8
references.pmid: 22101430
references.citation: Nature. 2011 Oct 23;479(7373):401-5
references.pmid: 22020283
references.citation: Blood. 2011 Dec 8;118(24):6387-91
references.pmid: 22031859
references.citation: J Immunol. 2004 Jan 15;172(2):864-70
references.pmid: 14707057
references.citation: Blood. 2011 Jan 6;117(1):98-107
references.pmid: 20935255
references.citation: N Engl J Med. 2011 Aug 25;365(8):725-33
references.pmid: 21830940
references.citation: Cancer Immunol Immunother. 2008 Mar;57(3):411-23
references.pmid: 17717662
references.citation: Int J Cancer. 2006 Jan 1;118(1):129-38
references.pmid: 16003759
references.citation: Adv Hematol. 2012;2012:513702
references.pmid: 22888354
references.citation: Cancer Immunol Immunother. 2008 Dec;57(12):1849-59
references.pmid: 18392823
references.citation: Cancer Gene Ther. 2010 Mar;17(3):147-54
references.pmid: 19745843
references.citation: Nat Rev Immunol. 2013 Feb;13(2):75-87
references.pmid: 23292121
references.citation: Science. 2004 Aug 6;305(5685):872-4
references.pmid: 15297676
references.citation: Blood. 2009 Sep 24;114(13):2667-77
references.pmid: 19553639
references.citation: Science. 1991 Jul 12;253(5016):199-202
references.pmid: 1853205
references.citation: Hum Immunol. 1999 Jan;60(1):32-40
references.pmid: 9952025
references.citation: Nat Rev Immunol. 2013 Feb;13(2):145-9
references.pmid: 23348417
references.citation: Transfusion. 2013 Feb;53(2):412-8; quiz 411
references.pmid: 22738379
references.citation: Cytotherapy. 2008;10(6):625-32
references.pmid: 18836917
references.citation: Hum Immunol. 2007 May;68(5):309-23
references.pmid: 17462498
references.citation: Immunol Today. 1990 Jul;11(7):237-44
references.pmid: 2201309
references.citation: Curr Opin Immunol. 2011 Feb;23(1):96-103
references.pmid: 21146386
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1915-9
references.pmid: 19181844
references.citation: PLoS Biol. 2011 Nov;9(11):e1001208
references.pmid: 22140359
references.citation: Blood. 2011 Feb 3;117(5):1605-13
references.pmid: 20978269
references.citation: Transfusion. 2013 Feb;53(2):404-10
references.pmid: 22670662
references.citation: J Exp Med. 2009 Jul 6;206(7):1495-503
references.pmid: 19528259
references.citation: J Exp Med. 2012 Dec 17;209(13):2351-65
references.pmid: 23209317
references.citation: Blood. 2012 Nov 22;120(22):4324-33
references.pmid: 23033266
references.citation: Nat Immunol. 2006 May;7(5):507-16
references.pmid: 16617337
references.citation: Nat Rev Immunol. 2006 Jul;6(7):520-31
references.pmid: 16799471
references.citation: Biol Blood Marrow Transplant. 2010 Sep;16(9):1257-64
references.pmid: 20302958
references.citation: J Immunol. 2010 Sep 1;185(5):2918-26
references.pmid: 20675589
references.citation: Blood. 2012 Nov 1;120(18):3729-40
references.pmid: 22966166
references.citation: J Cancer. 2011;2:383-5
references.pmid: 21750690
references.citation: J Exp Med. 2003 Apr 21;197(8):977-84
references.pmid: 12695489
references.citation: Blood. 2011 Nov 3;118(18):4817-28
references.pmid: 21849486
references.citation: Nat Immunol. 2010 Dec;11(12):1127-35
references.pmid: 20972432
references.citation: Blood. 2010 Oct 7;116(14):2411-9
references.pmid: 20581313
references.citation: Nature. 2005 Aug 4;436(7051):709-13
references.pmid: 16079848
references.citation: J Leukoc Biol. 2013 Oct;94(4):671-5
references.pmid: 23250891
references.citation: N Engl J Med. 2012 Aug 30;367(9):805-16
references.pmid: 22931314
references.citation: Curr Cancer Drug Targets. 2011 Mar;11(3):239-53
references.pmid: 21247388
references.citation: Blood. 2008 Aug 1;112(3):461-9
references.pmid: 18650461
references.citation: Blood. 2007 Jul 15;110(2):578-86
references.pmid: 17392508
references.citation: J Exp Med. 2003 Apr 21;197(8):967-76
references.pmid: 12695488
references.citation: Front Immunol. 2013 Mar 27;4:76
references.pmid: 23543707
references.citation: J Exp Med. 2011 Feb 14;208(2):357-68
references.pmid: 21262959
references.citation: Science. 2002 Mar 15;295(5562):2097-100
references.pmid: 11896281
references.citation: J Immunol. 2009 May 15;182(10):6426-34
references.pmid: 19414796
references.citation: Trends Immunol. 2002 Sep;23(9):438-44
references.pmid: 12200065
references.citation: Blood. 2009 Mar 12;113(11):2434-41
references.pmid: 18974374
references.citation: Front Immunol. 2012 Nov 09;3:335
references.pmid: 23162553
references.citation: J Exp Med. 2004 Oct 18;200(8):957-65
references.pmid: 15477349
references.citation: Front Immunol. 2013 Jan 03;3:388
references.pmid: 23316191
references.citation: Br J Haematol. 2005 Jan;128(2):192-203
references.pmid: 15638853
references.citation: Curr Top Microbiol Immunol. 2006;298:23-57
references.pmid: 16329184
references.citation: Nat Immunol. 2004 Dec;5(12):1260-5
references.pmid: 15531883
references.citation: Blood. 1999 Jul 1;94(1):333-9
references.pmid: 10381530
references.citation: J Immunol. 2008 May 1;180(9):6392-401
references.pmid: 18424763
references.citation: Blood. 2013 Apr 4;121(14):2678-88
references.pmid: 23325834
references.citation: Science. 1999 Jul 30;285(5428):727-9
references.pmid: 10426993
references.citation: Blood. 2003 Apr 15;101(8):3052-7
references.pmid: 12480696
references.citation: Immunol Rev. 1997 Feb;155:41-52
references.pmid: 9059881
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12879-84
references.pmid: 19561305
references.citation: Tissue Antigens. 2007 Apr;69 Suppl 1:42-5
references.pmid: 17445161
references.citation: Blood. 2011 Feb 24;117(8):2423-32
references.pmid: 21193697
references.citation: Blood. 2012 Mar 15;119(11):2665-74
references.pmid: 22180440
references.citation: Blood. 2012 Dec 6;120(24):4751-60
references.pmid: 22983442
references.citation: Blood. 2005 Jul 1;106(1):376-83
references.pmid: 15755898
references.citation: J Immunol. 2009 Apr 15;182(8):4572-80
references.pmid: 19342631
references.citation: J Clin Oncol. 2010 Feb 20;28(6):955-9
references.pmid: 20085940
references.citation: Blood. 2012 Mar 22;119(12):2709-20
references.pmid: 22160384
references.citation: Nat Immunol. 2010 Apr;11(4):321-7
references.pmid: 20190757
references.citation: Blood. 2010 Mar 18;115(11):2167-76
references.pmid: 19965656
references.citation: Blood. 2009 Jun 11;113(24):6120-7
references.pmid: 19202127
references.citation: Immunity. 2006 Aug;25(2):331-42
references.pmid: 16901727
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3053-8
references.pmid: 18287063
references.citation: Clin Cancer Res. 2009 Aug 1;15(15):4857-66
references.pmid: 19638467
references.citation: Genes Immun. 2007 Apr;8(3):245-53
references.pmid: 17315044
references.citation: Blood. 2002 Aug 15;100(4):1265-73
references.pmid: 12149207
references.citation: J Immunol. 2010 Aug 15;185(4):2009-12
references.pmid: 20631304
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14725-32
references.pmid: 21825173
references.citation: Nat Rev Immunol. 2005 Mar;5(3):201-14
references.pmid: 15719024
references.citation: Blood. 2005 Apr 15;105(8):3051-7
references.pmid: 15632206
references.citation: Blood. 2010 Sep 30;116(13):2286-94
references.pmid: 20460501
references.citation: Nature. 2009 Jan 29;457(7229):557-61
references.pmid: 19136945
references.citation: Blood. 2011 Sep 22;118(12):3273-9
references.pmid: 21791425
references.citation: Annu Rev Immunol. 2001;19:197-223
references.pmid: 11244035
references.citation: Curr Opin Allergy Clin Immunol. 2006 Dec;6(6):399-409
references.pmid: 17088643
references.citation: Clin Cancer Res. 2008 Jun 1;14(11):3520-8
references.pmid: 18519785
references.citation: Nat Immunol. 2008 May;9(5):503-10
references.pmid: 18425107
references.citation: Cell Mol Immunol. 2011 Jan;8(1):1-11
references.pmid: 20711229
references.citation: J Immunol. 2011 Sep 1;187(5):2162-71
references.pmid: 21804024
references.citation: Immunol Rev. 2001 Jun;181:79-89
references.pmid: 11513154
references.citation: Immunity. 2009 Mar 20;30(3):337-47
references.pmid: 19249231
references.citation: Eur J Immunol. 2001 Nov;31(11):3370-9
references.pmid: 11745355
references.citation: Blood. 2007 Jun 1;109(11):5058-61
references.pmid: 17317850
references.citation: J Immunol. 2006 Feb 1;176(3):1517-24
references.pmid: 16424180
references.citation: Blood. 2012 Nov 22;120(22):4317-23
references.pmid: 23002117
references.citation: Nat Genet. 2007 Jun;39(6):733-40
references.pmid: 17496894
references.citation: Blood. 2005 Jun 1;105(11):4416-23
references.pmid: 15728129
references.citation: Blood. 2010 Aug 26;116(8):1272-9
references.pmid: 20472831