Stromal cells (SC) are an important component of decidual tissues where they are in strict proximity with both NK and CD14+ myelomonocytic cells that play a role in the maintenance of pregnancy. In this study we analyzed whether decidual SC (DSC) could exert a regulatory role on NK and CD14+ cells that migrate from peripheral blood (PB) to decidua during pregnancy. We show that DSCs inhibit the IL15-mediated up-regulation of major activating NK receptors in PB-derived NK cells. In addition, the IL15-induced NK cell proliferation, cytolytic activity and IFN-γ production were severely impaired. DSCs sharply inhibited dendritic cells differentiation and their ability to induce allogeneic T cell proliferation. Indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2) mediated the inhibitory effect of DSCs. Our results strongly suggest an important role of DSCs in preventing potentially dangerous immune response, thus contributing to maintenance of pregnancy.
References
[1]
Caligiuri MA (2008) Human natural killer cells. Blood 112: 461–469. doi: 10.1182/blood-2007-09-077438
[2]
Cerwenka A, Lanier LL (2001) Natural killer cells, viruses and cancer. Nat Rev Immunol 1: 41–49. doi: 10.1038/35095564
[3]
Fauriat C, Long EO, Ljunggren HG, Bryceson YT (2010) Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood 115: 2167–2176. doi: 10.1182/blood-2009-08-238469
[4]
Le Bouteiller P, Tabiasco J (2006) Killers become builders during pregnancy. Nat Med 12: 991–992. doi: 10.1038/nm0906-991
[5]
Moretta A (2002) Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2: 957–964. doi: 10.1038/nri956
[6]
Moretta A, Bottino C, Vitale M, Pende D, Biassoni R, et al. (1996) Receptors for HLA class-I molecules in human natural killer cells. Annu Rev Immunol 14: 619–648. doi: 10.1146/annurev.immunol.14.1.619
[7]
Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, et al. (2001) Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19: 197–223. doi: 10.1034/j.1600-065x.2001.1810117.x
[8]
Moretta L, Moretta A (2004) Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J 23: 255–259. doi: 10.1038/sj.emboj.7600019
[9]
Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23: 225–274. doi: 10.1146/annurev.immunol.23.021704.115526
[10]
Moffett-King A (2002) Natural killer cells and pregnancy. Nat Rev Immunol 2: 656–663. doi: 10.1038/nri886
[11]
Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, et al. (2006) Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 12: 1065–1074. doi: 10.1038/nm1452
[12]
Bulmer JN, Williams PJ, Lash GE (2010) Immune cells in the placental bed. Int J Dev Biol 54: 281–294. doi: 10.1387/ijdb.082763jb
[13]
Hanna J, Mandelboim O (2007) When killers become helpers. Trends Immunol 28: 201–206. doi: 10.1016/j.it.2007.03.005
[14]
Manaster I, Mandelboim O (2010) The unique properties of uterine NK cells. Am J Reprod Immunol 63: 434–444. doi: 10.1111/j.1600-0897.2009.00794.x
[15]
Vacca P, Cantoni C, Prato C, Fulcheri E, Moretta A, et al. (2008) Regulatory role of NKp44, NKp46, DNAM-1 and NKG2D receptors in the interaction between NK cells and trophoblast cells. Evidence for divergent functional profiles of decidual versus peripheral NK cells. Int Immunol 20: 1395–1405. doi: 10.1093/intimm/dxn105
[16]
Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, et al. (2003) Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 198: 1201–1212. doi: 10.1084/jem.20030305
[17]
Vacca P, Pietra G, Falco M, Romeo E, Bottino C, et al. (2006) Analysis of natural killer cells isolated from human decidua: Evidence that 2B4 (CD244) functions as an inhibitory receptor and blocks NK-cell function. Blood 108: 4078–4085. doi: 10.1182/blood-2006-04-017343
[18]
Kopcow HD, Allan DS, Chen X, Rybalov B, Andzelm MM, et al. (2005) Human decidual NK cells form immature activating synapses and are not cytotoxic. Proc Natl Acad Sci U S A 102: 15563–15568. doi: 10.1073/pnas.0507835102
[19]
Moffett A, Loke C (2006) Immunology of placentation in eutherian mammals. Nat Rev Immunol 6: 584–594. doi: 10.1038/nri1897
[20]
Vacca P, Moretta L, Moretta A, Mingari MC (2011) Origin, phenotype and function of human natural killer cells in pregnancy. Trends Immunol 32: 517–523. doi: 10.1016/j.it.2011.06.013
[21]
Robson A, Harris LK, Innes BA, Lash GE, Aljunaidy MM, et al. (2012) Uterine natural killer cells initiate spiral artery remodeling in human pregnancy. FASEB J 26: 4876–4885. doi: 10.1096/fj.12-210310
[22]
Vacca P, Vitale C, Montaldo E, Conte R, Cantoni C, et al. (2011) CD34+ hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells. Proc Natl Acad Sci U S A 108: 2402–2407. doi: 10.1073/pnas.1016257108
[23]
Manaster I, Mizrahi S, Goldman-Wohl D, Sela HY, Stern-Ginossar N, et al. (2008) Endometrial NK cells are special immature cells that await pregnancy. J Immunol 181: 1869–1876. doi: 10.4049/jimmunol.181.3.1869
[24]
Carlino C, Stabile H, Morrone S, Bulla R, Soriani A, et al. (2008) Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy. Blood 111: 3108–3115. doi: 10.1182/blood-2007-08-105965
[25]
Male V, Hughes T, McClory S, Colucci F, Caligiuri MA, et al. (2010) Immature NK cells, capable of producing IL-22, are present in human uterine mucosa. J Immunol 185: 3913–3918. doi: 10.4049/jimmunol.1001637
[26]
Keskin DB, Allan DS, Rybalov B, Andzelm MM, Stern JN, et al. (2007) TGFbeta promotes conversion of CD16+ peripheral blood NK cells into CD16- NK cells with similarities to decidual NK cells. Proc Natl Acad Sci U S A 104: 3378–3383. doi: 10.1073/pnas.0611098104
[27]
Kammerer U, Eggert AO, Kapp M, McLellan AD, Geijtenbeek TB, et al. (2003) Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy. Am J Pathol 162: 887–896. doi: 10.1016/s0002-9440(10)63884-9
[28]
Laskarin G, Cupurdija K, Tokmadzic VS, Dorcic D, Dupor J, et al. (2005) The presence of functional mannose receptor on macrophages at the maternal-fetal interface. Hum Reprod 20: 1057–1066. doi: 10.1093/humrep/deh740
[29]
Gustafsson C, Mjosberg J, Matussek A, Geffers R, Matthiesen L, et al. (2008) Gene expression profiling of human decidual macrophages: evidence for immunosuppressive phenotype. PLoS One 3: e2078. doi: 10.1371/journal.pone.0002078
[30]
Laskarin G, Redzovic A, Rubesa Z, Mantovani A, Allavena P, et al. (2008) Decidual natural killer cell tuning by autologous dendritic cells. Am J Reprod Immunol 59: 433–445. doi: 10.1111/j.1600-0897.2008.00599.x
[31]
Vacca P, Cantoni C, Vitale M, Prato C, Canegallo F, et al. (2010) Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression. Proc Natl Acad Sci U S A 107: 11918–11923. doi: 10.1073/pnas.1001749107
[32]
Saito S, Sakai M, Sasaki Y, Nakashima A, Shiozaki A (2007) Inadequate tolerance induction may induce pre-eclampsia. J Reprod Immunol 76: 30–39. doi: 10.1016/j.jri.2007.08.002
[33]
Heikkinen J, Mottonen M, Alanen A, Lassila O (2004) Phenotypic characterization of regulatory T cells in the human decidua. Clin Exp Immunol 136: 373–378. doi: 10.1111/j.1365-2249.2004.02441.x
[34]
Erkers T, Nava S, Yosef J, Ringden O, Kaipe H (2013) Decidual stromal cells promote regulatory T cells and suppress alloreactivity in a cell contact-dependent manner. Stem Cells Dev 22: 2596–2605. doi: 10.1089/scd.2013.0079
[35]
Gronthos S, Franklin DM, Leddy HA, Robey PG, Storms RW, et al. (2001) Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol 189: 54–63. doi: 10.1002/jcp.1138
[36]
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, et al. (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284: 143–147. doi: 10.1126/science.284.5411.143
[37]
Deans RJ, Moseley AB (2000) Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 28: 875–884. doi: 10.1016/s0301-472x(00)00482-3
[38]
Uccelli A, Moretta L, Pistoia V (2006) Immunoregulatory function of mesenchymal stem cells. Eur J Immunol 36: 2566–2573. doi: 10.1002/eji.200636416
[39]
Xu X, Wang Q, Deng B, Wang H, Dong Z, et al. (2012) Monocyte chemoattractant protein-1 secreted by decidual stromal cells inhibits NK cells cytotoxicity by up-regulating expression of SOCS3. PLoS One 7: e41869. doi: 10.1371/journal.pone.0041869
[40]
Olivares EG, Montes MJ, Oliver C, Galindo JA, Ruiz C (1997) Cultured human decidual stromal cells express B7–1 (CD80) and B7–2 (CD86) and stimulate allogeneic T cells. Biol Reprod 57: 609–615. doi: 10.1095/biolreprod57.3.609
[41]
Balsamo M, Scordamaglia F, Pietra G, Manzini C, Cantoni C, et al. (2009) Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc Natl Acad Sci U S A 106: 20847–20852. doi: 10.1073/pnas.0906481106
[42]
Dokic J, Tomic S, Markovic M, Milosavljevic P, Colic M (2013) Mesenchymal stem cells from periapical lesions modulate differentiation and functional properties of monocyte-derived dendritic cells. Eur J Immunol 43: 1862–1872. doi: 10.1002/eji.201243010
[43]
Erices A, Conget P, Minguell JJ (2000) Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 109: 235–242. doi: 10.1046/j.1365-2141.2000.01986.x
[44]
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, et al. (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99: 3838–3843. doi: 10.1182/blood.v99.10.3838
[45]
Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, et al. (2008) Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111: 1327–1333. doi: 10.1182/blood-2007-02-074997
[46]
Spaggiari GM, Abdelrazik H, Becchetti F, Moretta L (2009) MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 113: 6576–6583. doi: 10.1182/blood-2009-02-203943
[47]
Liotta F, Angeli R, Cosmi L, Fili L, Manuelli C, et al. (2008) Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells 26: 279–289. doi: 10.1634/stemcells.2007-0454
[48]
Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, et al. (2004) Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117: 515–526. doi: 10.1016/s0092-8674(04)00451-9
[49]
Manaster I, Gazit R, Goldman-Wohl D, Stern-Ginossar N, Mizrahi S, et al. (2010) Notch activation enhances IFNgamma secretion by human peripheral blood and decidual NK cells. J Reprod Immunol 84: 1–7. doi: 10.1016/j.jri.2009.10.009
[50]
He YY, He XJ, Guo PF, Du MR, Shao J, et al. (2012) The decidual stromal cells-secreted CCL2 induces and maintains decidual leukocytes into Th2 bias in human early pregnancy. Clin Immunol 145: 161–173. doi: 10.1016/j.clim.2012.07.017
[51]
Kayisli UA, Selam B, Guzeloglu-Kayisli O, Demir R, Arici A (2003) Human chorionic gonadotropin contributes to maternal immunotolerance and endometrial apoptosis by regulating Fas-Fas ligand system. J Immunol 171: 2305–2313. doi: 10.4049/jimmunol.171.5.2305
[52]
D’Urso CM, Wang ZG, Cao Y, Tatake R, Zeff RA, et al. (1991) Lack of HLA class I antigen expression by cultured melanoma cells FO-1 due to a defect in B2m gene expression. J Clin Invest 87: 284–292. doi: 10.1172/jci114984
[53]
Wang Z, Hu XZ, Tatake RJ, Yang SY, Zeff RA, et al. (1993) Differential effect of human and mouse beta 2-microglobulin on the induction and the antigenic profile of endogenous HLA-A and -B antigens synthesized by beta 2-microglobulin gene-null FO-1 melanoma cells. Cancer Res 53: 4303–4309.
[54]
Can A, Tekelioglu M, Baltaci A (1995) Expression of desmin and vimentin intermediate filaments in human decidual cells during first trimester pregnancy. Placenta 16: 261–275. doi: 10.1016/0143-4004(95)90113-2
[55]
Oliver C, Montes MJ, Galindo JA, Ruiz C, Olivares EG (1999) Human decidual stromal cells express alpha-smooth muscle actin and show ultrastructural similarities with myofibroblasts. Hum Reprod 14: 1599–1605. doi: 10.1093/humrep/14.6.1599
[56]
Rutz S, Mordmuller B, Sakano S, Scheffold A (2005) Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells. Eur J Immunol 35: 2443–2451. doi: 10.1002/eji.200526294
[57]
Vacca P, Mingari MC, Moretta L (2013) Natural killer cells in human pregnancy. J Reprod Immunol 97: 14–19. doi: 10.1016/j.jri.2012.10.008