title: Maternal decidual macrophages inhibit NK cell killing of invasive cytotrophoblasts during human pregnancy.
abstract: Human pregnancy is an immunological paradox. Semiallogeneic (fetal) placental cells (extravillous cytotrophoblasts [CTBs]) invade the uterine lining (decidua), which contains a unique decidual natural killer (dNK) cell population, identified by the cell surface phenotype CD56(bright) CD16(-) CD3(-) and CD14(+) CD206(+) macrophages (dMac). Previous reports suggested that human dNK cells are not a threat to the fetoplacental unit because they are anergic. In contrast, here we showed that purified and exogenously stimulated dNK cells are capable killers of cellular targets, including semiallogeneic CTBs. However, dMacs in the decidual leukocyte (DL) population restrained dNK killing through a transforming growth factor beta1 (TGF-beta1)-dependent mechanism. Our findings support a new model whereby dNK cells, capable of killing CTBs, are prevented from doing so by neighboring macrophages, thus protecting the fetal cells from NK cell attack. We speculate that this mechanism would inhibit dNK cell-mediated killing, even under conditions where high levels of cytokines may stimulate dNK cells, which could pose a threat to the developing placenta.
authors.affiliation: Department of Obstetrics, Center for Reproductive Sciences, Division of Maternal Fetal Medicine, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Co
authors.forename: Matthew
authors.initials: M
authors.lastname: Gormley
authors.forename: Mirhan
authors.initials: M
authors.lastname: Kapidzic
authors.forename: David B
authors.initials: DB
authors.lastname: Rosen
authors.forename: Marvin A
authors.initials: MA
authors.lastname: Scott
authors.forename: Haley A R
authors.initials: HA
authors.lastname: Stolp
authors.forename: Michael
authors.initials: M
authors.lastname: McMaster
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Alicia
authors.initials: A
authors.lastname: Bárcena
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Fisher
mesh_terms: D017252:CD3 Complex / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D019002:CD56 Antigen; D037181:Lectins, C-Type; D018950:Lipopolysaccharide Receptors; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D017452:Receptors, IgG
keywords: decidua; macrophage; natural killer cells; placenta; pregnancy; trophoblast
references.citation: J Clin Invest. 2007 May;117(5):1155-66
references.pmid: 17476345
references.citation: J Immunol. 1986 May 15;136(10):3916-20
references.pmid: 2871107
references.citation: Nat Rev Immunol. 2002 Sep;2(9):656-63
references.pmid: 12209134
references.citation: J Immunol. 2011 Feb 15;186(4):2633-42
references.pmid: 21257965
references.citation: Annu Rev Immunol. 2009;27:451-83
references.pmid: 19105661
references.citation: Mol Immunol. 2004 Nov;41(11):1109-21
references.pmid: 15476922
references.citation: Placenta. 2002 Apr;23(4):274-80
references.pmid: 11969337
references.citation: J Immunol. 1990 Jan 15;144(2):731-5
references.pmid: 2295808
references.citation: Nat Med. 1997 Jun;3(6):610-1
references.pmid: 9176484
references.citation: Annu Rev Immunol. 2013;31:387-411
references.pmid: 23298207
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):728-32
references.pmid: 21187373
references.citation: Novartis Found Symp. 2004;256:158-68; discussion 168-72, 259-69
references.pmid: 15027489
references.citation: J Immunol. 2003 Sep 15;171(6):2937-44
references.pmid: 12960317
references.citation: Biol Reprod. 1997 Nov;57(5):1217-22
references.pmid: 9369190
references.citation: Fertil Steril. 2003 Apr;79(4):856-63
references.pmid: 12749421
references.citation: J Immunol. 2004 Jun 15;172(12):7335-40
references.pmid: 15187109
references.citation: PLoS One. 2008 Apr 30;3(4):e2078
references.pmid: 18446208
references.citation: J Exp Med. 2005 Oct 17;202(8):1075-85
references.pmid: 16230475
references.citation: Biol Reprod. 2000 Apr;62(4):959-68
references.pmid: 10727265
references.citation: Biol Reprod. 1992 Apr;46(4):561-72
references.pmid: 1374270
references.citation: Am J Reprod Immunol. 2004 Oct;52(4):244-51
references.pmid: 15494045
references.citation: J Immunol. 2005 Oct 15;175(8):5541-50
references.pmid: 16210663
references.citation: J Clin Invest. 1982 Apr;69(4):876-88
references.pmid: 7076851
references.citation: Proc Natl Acad Sci U S A. 1999 May 11;96(10):5343-5
references.pmid: 10318882
references.citation: Mol Hum Reprod. 2011 Sep;17(9):577-86
references.pmid: 21471023
references.citation: Reprod Biol Endocrinol. 2003 Dec 02;1:119
references.pmid: 14651752
references.citation: Hum Reprod. 2008 Jun;23(6):1447-56
references.pmid: 18434375
references.citation: Science. 1997 Sep 12;277(5332):1669-72
references.pmid: 9287221
references.citation: Dev Biol. 2006 Oct 1;298(1):107-17
references.pmid: 16930583
references.citation: Methods Enzymol. 2008;445:281-302
references.pmid: 19022064
references.citation: Biol Reprod. 2011 Oct;85(4):788-97
references.pmid: 21734258
references.citation: Annu Rev Immunol. 2005;23:225-74
references.pmid: 15771571
references.citation: Am J Pathol. 1999 Jul;155(1):293-301
references.pmid: 10393861
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15563-8
references.pmid: 16230631
references.citation: Cancer Immunol Immunother. 1988;26(2):95-100
references.pmid: 2452015
references.citation: J Exp Med. 2001 May 21;193(10):1199-212
references.pmid: 11369791
references.citation: J Immunol. 2011 Oct 1;187(7):3671-82
references.pmid: 21890660
references.citation: Placenta. 2011 Jan;32(1):33-43
references.pmid: 21075446
references.citation: Anal Biochem. 1994 Feb 1;216(2):276-84
references.pmid: 8179182
references.citation: Nature. 2012 Oct 4;490(7418):102-6
references.pmid: 23023128
references.citation: J Exp Med. 1994 Jul 1;180(1):123-32
references.pmid: 7516402
references.citation: Science. 1990 Apr 13;248(4952):220-3
references.pmid: 2326636
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11918-23
references.pmid: 20547831
references.citation: J Immunol. 1998 Jun 15;160(12):5922-8
references.pmid: 9637505
references.citation: J Immunol. 1994 May 1;152(9):4255-61
references.pmid: 8157952
references.citation: Immunol Rev. 2001 Jun;181:170-84
references.pmid: 11513138
references.citation: Trends Immunol. 2003 May;24(5):235-41
references.pmid: 12738416
references.citation: J Exp Med. 1993 Sep 1;178(3):1041-8
references.pmid: 8102388
references.citation: J Exp Med. 2003 Oct 20;198(8):1201-12
references.pmid: 14568979
references.citation: Clin Exp Immunol. 2003 Mar;131(3):498-505
references.pmid: 12605704
references.citation: Blood. 2001 May 15;97(10):3146-51
references.pmid: 11342442
references.citation: J Immunol. 2008 Aug 1;181(3):1869-76
references.pmid: 18641324
references.citation: Am J Med Genet A. 2004 Nov 1;130A(4):354-64
references.pmid: 15389712
references.citation: Science. 2012 Jun 8;336(6086):1317-21
references.pmid: 22679098
references.citation: J Immunol. 1991 Oct 15;147(8):2717-27
references.pmid: 1918986
references.citation: Am J Pathol. 2008 Sep;173(3):653-64
references.pmid: 18688023
references.citation: Cell. 2012 Jul 6;150(1):29-38
references.pmid: 22770213
references.citation: J Exp Med. 2000 Jul 17;192(2):259-70
references.pmid: 10899912
references.citation: Nat Rev Immunol. 2005 Dec;5(12):953-64
references.pmid: 16322748
references.citation: J Immunol. 2003 Feb 15;170(4):1763-9
references.pmid: 12574340
references.citation: J Reprod Immunol. 2010 Jun;85(2):130-9
references.pmid: 20478621
references.citation: Hum Reprod Update. 2007 Mar-Apr;13(2):121-41
references.pmid: 17068222
references.citation: Cell. 1992 Oct 30;71(3):355-7
references.pmid: 1423599
references.citation: J Immunol. 1995 Apr 15;154(8):3771-8
references.pmid: 7706718
references.citation: Clin Exp Immunol. 2005 Dec;142(3):481-9
references.pmid: 16297160
references.citation: J Immunol Methods. 1990 Sep 14;132(2):181-9
references.pmid: 2145368
references.citation: J Immunol. 2009 Jan 1;182(1):240-9
references.pmid: 19109155
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16940-5
references.pmid: 12486249