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Cellular & Molecular Immunology (2014) 11, 449–455 ß 2014 CSI and USTC. All rights reserved 1672-7681/14 $32.00 www.nature.com/cmi

REVIEW

Liaison between natural killer cells and dendritic cells in human gestation Ester Leno-Dura´n1,5, Raquel Mun˜oz-Ferna´ndez2,5, Enrique Garcı´a Olivares1,3 and Irene Tirado-Gonza´lez1,4 A successful pregnancy relies on immunological adaptations that allow the fetus to grow and develop in the uterus, despite being recognized by maternal immune cells. Among several immunocompetent cell types present within the human maternal/fetal interface, DC-SIGN1 dendritic cells (DCs) and CD561 natural killer (NK) cells are of major importance for early pregnancy maintenance, not only generating maternal immunological tolerance but also regulating stromal cell differentiation. Previous reports show the presence of NK–DC cell conjugates in first trimester human decidua, suggesting that these cells may play a role in the modulation of the local immune response within the uterus. While effective immunity is necessary to protect the mother from harmful pathogens, some form of tolerance must be activated to avoid an immune response against fetal antigens. This review article discusses current evidence concerning the functions of DC and NK cells in pregnancy and their liaison in human decidua. Cellular & Molecular Immunology (2014) 11, 449–455; doi:10.1038/cmi.2014.36; published online 23 June 2014 Keywords: cross-talk; dendritic cells; natural killer cells; pregnancy

INTRODUCTION Human pregnancy is a complex process whereby interactions between fetal trophoblast cells and maternal decidual immune cells play an important role in the pregnancy outcome. In the beginning of a pregnancy, embryo implantation occurs during the mid-secretory phase of the menstrual cycle, known as the ‘implantation window’. During this period, there are significant morphologic and functional changes in the maternal endometrium called decidualization. Decidual tissue plays both nutritional and endocrine roles in pregnancy by producing cytokines, supporting implantation and embryo growth, and maintaining early pregnancy, as well as harboring important immune cells for fetomaternal interface immunology.1,2 A successful pregnancy relies on immune adaptations that allow the fetus to grow and develop in the uterus, while effective immunity is necessary to protect the mother from harmful pathogens. It is widely understood that an inadequate microenvironment within the decidual tissue or a failure in the recognition of the fetal antigen can contribute to various pregnancy complications.2,3 In normal human pregnancies it is known 1

that among several immunocompetent cell types present within the human maternal-fetal interface, DC-SIGN1 immature dendritic cells (iDC) and CD561 natural killer cells (NK) are of particular importance for pregnancy maintenance and maternal immunological tolerance. Several studies indicate an intimate contact between iDCs and NK cells5,6 in the first trimester decidua, suggesting a pregnancyspecific interaction of these cells and their role in the modulation of the local immune response within the decidualized uterus. In vitro studies in mice showed that the differentiation and proliferation of uterine stroma cells during implantation is dependent on DC–NK cell cross-talk.7 Using cocultured trophoblast and uterine cells, it was found that when mouse DCs, NK cells or both cells types were depleted, the trophoblast-induced uterine cell proliferation was decreased.7 DCs appear to play a pivotal role in promoting NK cell differentiation, as highlighted by in vivo studies describing impaired NK cell function in DCdepleted implantation sites. Animals in these studies present low levels of interleukin (IL)-15 resulting in reduced numbers of and impaired differentiation of NK cells.9 Moreover, this

Instituto de Biopatologı´a y Medicina Regenerativa, Centro de Investigacio´n Biome´dica, Universidad de Granada, Armilla, Granada, Spain; 2Instituto de Parasitologı´a y Biomedicina ‘Lo´pez Neyra’, Centro superior de investigaciones cientı´ficas, Armilla, Granada, Spain; 3Hospital Universitario San Cecilio, Granada, Spain and 4Medicine University of Berlin, Charite´ Centre 12 Internal Medicine and Dermatology, Berlin, Germany 5 These authors contributed equally to this work. Correspondence: Dr I Tirado-Gonza´lez, Instituto de Biopatologı´a y Medicina Regenerativa, Centro de Investigacio´n Biome´dica, University of Granada, Armilla, Granada, Spain. E-mail: [email protected] Received: 10 March 2014; Revised: 29 April 2014; Accepted: 1 May 2014

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causes a reduction in interferon-c levels and therefore an inadequate spiral artery remodeling.8,9 Additionally, murine data indicate that NK cells are also critical for DC immunogenic functions during pregnancy; NK cell ablation in Fms-related tyrosine kinase 3 ligand-expanded DC mice severely compromised decidual development, upregulated anti-angiogenic growth factors expression such as sFlt1 and PF4, generated an inflammatory environment and led to early pregnancy loss.10 Although studies with mice demonstrate the importance of DC–NK cell cross-talk, data from human research provide conflicting results. Human iDCs can induce NK cell proliferation and cytotoxicity, and, reciprocally, NK cells can induce apoptotic DC death.6,11 Activated NK cells kill decidual iDCs through apoptosis, which benefits normal pregnancy by preventing the formation of mature dendritic cells (mDCs)12 and controlling unwanted Th1 immune responses.6 Although it is clear that the interaction between DC and NK cells is important for a healthy pregnancy, the current literature lacks a comprehensive summary on this topic. The aim of this review is to summarize the current information concerning the pregnancyrelated functions and phenotypes of DCs and NK cells, and their liaison during human gestation. HUMAN DCS Human peripheral blood DCs are categorized as either myeloid CD142CD11c1 or plasmacytoid, CD1231CD11c2. Myeloid DCs are the major peripheral blood subtype and are able to stimulate a Th1 response, whereas plasmacytoid DCs generate only Th2 responses.13 Peripheral myeloid DCs contribute to tolerance during normal pregnancy by activating regulatory T cells to produce IL-10 and transforming growth factorbeta.14,15 Peripheral myeloid DCs, which are highly tolerogenic during the first trimester, undergo a state of partial inactivation during the third trimester with the population size decreasing before delivery.14 These cells play a prominent role during early pregnancy in the maintenance of fetal tolerance.16 Peripheral myeloid DCs can migrate into different tissues, such as the endometrium, where they are retained as sentinels in an immature stage.4 iDCs existing in the human non-pregnant endometrium are characterized by DC-SIGN (DC-specific intercellular adhesion molecule 3–grabbing nonintegrin) expression, and represent approximately 5%–10% of all hematopoietic cells.5,17 The presence of these immature DCSIGN1 cells in the endometrium, and their maturation to mDC CD831 cells upon exposure to antigens or inflammatory cytokines during the menstrual cycle, suggest that these are likely involved in the uterine defense against pathogens.17 Following conception, first trimester human decidual tissue contains mainly DCs of myeloid origin, but not plasmacytoid DCs.20,64 mDCs are further subdivided into a predominant population of immature DC-SIGN1 cells, which increase during pregnancy development,18 and a smaller population of mature CD83-expressing cells.5,17 These observations suggest that full decidualization in response to the implantation and placentation processes is associated with a decline in CD831 cells and an increase in DC-SIGN1 DCs. After fetal antigen Cellular & Molecular Immunology

uptake, DC-SIGN1 cells differentiate into mature CD831 cells, migrate to the secondary lymphoid organs and stimulate the resident T-cell population.19,20 The iDCs expressing DC-SIGN exhibit considerable plasticity in their ability to promote T helper responses, and, in addition to their protective function, there is evidence that these cells are also involved in generating maternal tolerance to fetal antigens.5 Supporting this notion, Hsu and colleagues have described that DC-SIGN1 cells induce regulatory T cells during pregnancy.21 DC-SIGN1 DCs are also able to secrete IL-15 during decidualization and embryo implantation.11,22 This secretion then recruits decidual NK cells to the endometrium23 and upregulates CD56 expression.24 Previous works state that decidua tissues from spontaneous abortions contain fewer DC-SIGN1 iDCs compared with normal decidua, and iDC maturation and migration out of the decidual tissue to initiate an immune response might explain this phenomenon.20 Evidence for this hypothesis is also seen in preeclampsia studies, which demonstrated that although DC-SIGN1 iDCs are greatly increased, they display a poor capacity to induce regulatory T cells and, subsequently, to control detrimental Th1 responses.21 Many types of DC subsets have also been described to contribute to tolerance in pregnancy. Tolerogenic DCs can be generated either in the absence of stimulatory signals or after exposure to an anti-inflammatory milieu such as IL-10, progesterone, human chorionic gonadotropin or estradiol. Under these circumstances, tolerogenic DCs produce anti-inflammatory cytokines and develop an inhibitory phenotype, which prevents T-cell activation.25 Recently, a new subset of tolerogenic human DCs has been detected at the fetomaternal interface, the IL-10 producing DC (DC-10), which contributes to establishing tolerance and pregnancy maintenance.26 Additionally, two myeloid DC subsets have been characterized in human first trimester decidua, called myeloid type 1 and myeloid type 2.27 The myeloid type 2 cells are induced by IL10, increase in number during pregnancy27 and cannot recognize fetal antigens from the trophoblast (due to a lack of an Fc receptor), thus increasing maternal–fetal tolerance.28 It has been hypothesized that HLA-G is one of the most important tolerogenic molecules during pregnancy. Although HLA-G is preferentially expressed at high levels in trophoblasts, it is also expressed by decidual stromal cells (the major cellular population in human decidua),29 DC-10, CD41 T cells26 and DCSIGN1 iDCs.21 Stromal cell expression contributes to tolerance, not only because of their expression on the decidua but also via their interaction with dNK cells. HUMAN NK CELLS NK cells, representing 15% of peripheral blood lymphocytes and 70% of uterine lymphocytes, are the major leukocyte population present during the first trimester of pregnancy. Endometrial NK cells are present in non-pregnant endometrium and proliferate throughout the secretory phase of the menstrual cycle. During embryo implantation, NK cells continue to proliferate until the end of the first trimester (now referred to as decidual NK (dNK) cells). After the first trimester, the dNK cell count decreases, with a small population

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remaining at the end of gestation.18,30 Decidual NK cells are identified by their CD56bright CD162 cell surface phenotype,31 and although it is not currently known from where dNK cells originate, there are several hypotheses presently being considered. The hypotheses concerning the origin of dNK cells are as follows: recruitment of peripheral CD162 NK (pNK) cells; differentiation of CD161 pNK cells; differentiation from an immature NK precursor within the decidua; and maturation from CD341 progenitor cells. Of these hypotheses, the most widely accepted is that dNK cells are derived from CD56brightCD162 pNK cells that are recruited from the blood stream into decidual tissue. Similar to pNK CD56brightCD162 cells, dNK cells do not express CD16, they express the CD94/NKG2A inhibitory receptor, show reduced cytotoxic activity and efficiently produce cytokines, angiogenic growth factors62,63 and chemokines such as interferon (IFN)-c and tumor-necrosis factor (TNF)-a.32 However, there are also important differences between CD56bright pNK cells and their decidual counterparts. CD56bright dNK cells express the activation marker CD69,33 lack L-selectin (a molecule involved in adhesion and migration, which is shed upon extravasation),34 express killer immunoglobulin-like receptors and produce large amounts of perforin and granzymes.35,36 Second, it can also be argued that dNK cells are recruited from the CD56dimCD161 pNK population, which also express killer immunoglobulinlike receptors and high levels of cytotoxicity-associated molecules. Once in the decidual tissue, CD56dim cells can acquire a CD56bright profile. Furthermore, it has been demonstrated in vitro that transforming growth factor-b and IL-15 (which are present in human decidua) promote the conversion of CD56dimCD161 pNK cells into CD56dimCD162 NK cells with properties similar to decidual NK cells.37 Alternative data suggest that dNK cells originate from inside the decidua. Male et al. demonstrated that the immature dNK cell precursors differentiated to mature dNK cells and that the decidual microenvironment presents the appropriate conditions for this differentiation to occur.38 Other groups have suggested that dNK cells originate from decidual hematopoietic CD341 precursors, demonstrating in vitro that CD341 decidual cells cocultured with decidual stromal cells can differentiate into functional CD56brightCD162 NK cells.39 Differentiation of CD341 cells into CD56bright NK cells has also been demonstrated in other tissues, such as the lymph nodes.40 Recently, studies in mice have described two waves of distinct hematopoietic cells in the fetal thymus with potential to develop into NK cells.65 The different hypotheses regarding the origin of dNK cells are not mutually exclusive. Therefore, there may exist several ways by which dNK cells originate in order to participate in the different processes needed to support a successful pregnancy outcome. As they are localized to the area of embryo implantation, decidual CD561 NK cells are a primary source of the cytokines involved in trophoblast invasion, growth and angiogenesis, which are critical steps for a successful early pregnancy.31,32,41 Trophoblast invasion is a highly sensitive process, as either excess or insufficient invasion can result in pregnancy complications.

dNK cells, which are localized in close proximity to trophoblast cells, have the unique functional ability to support the trophoblast invasion process.42 In vitro studies with freshly isolated human trophoblasts confirmed that coculture of these cells with dNK cells increased the invasion and migration of trophoblast cells after 5 days compared with coculture with pNK cells.31 Human dNK cells also inhibit trophoblast invasion via cellmediated cytotoxicity and production of TNF-a, transforming growth factor-b1 and IFN-c.42,43 Decidual NK cells also participate in vascular remodeling and decidual angiogenesis during pregnancy, which are processes that are necessary for maximizing maternal blood flow to the placenta. These cells also seem to be crucial for maternal spiral arteries’ remodeling,44 and this event allows trophoblast cells to migrate through the vessels and invade the decidua.42 The growth and migration of human umbilical vascular endothelial cells in culture are increased by the presence of dNK cells and dependent on vascular endothelial growth factor and placenta growth factor.31 Furthermore, neutralization of these factors using an Flt1-Fc fusion protein inhibited the dNK cell angiogenic properties.31,41,42 In pregnancy pathogenesis, such as preeclampsia, intrauterine growth restriction and pregnancy loss, altered numbers of dNK cells are associated with reduced angiogenesis, defective vascular growth and reduced trophoblast invasion.45,46 In animal models, Croy and colleagues47 showed that NK-deficient mice have reduced placental blood supply compared with normal mice. Thus, NK cells are important for a healthy pregnancy outcome. NK–DC LIAISON While both DC and NK cells play important individual roles for a healthy pregnancy, the interaction of these two cell types show yet another facet of pregnancy maintenance (Figure 1). At the level of basic immunity, cross-talk between DC and NK cells plays an important role in the induction of both the innate and adaptive immune systems. In vitro studies using peripheral blood demonstrate that these cell types coordinate their responses by bidirectional cytokine cross-talk, as well as cell-tocell contact. Cytokines secreted by monocyte-derived mature DCs, such as IFNs, IL-15, IL-12 and IL-18, can activate NK cells, as well as enhance their proliferation, IFN-c secretion and cytotoxic capacity (Figure 1a).48 IFNs and cell-to-cell contact from DC-derived monocytes induces the expression of the NK cell activation marker CD69.49 Human DCs have also been shown to activate NK cells and increase their IFN-c production both in vitro and in vivo.50 IL-15 from DCs is also important for NK cell proliferation in both humans and mice. Interestingly, the action of this cytokine appears to require a membranebound form of IL-15 on mDCs and cell-to-cell contact, as NK cell proliferation was abrogated by blocking IL-15 and by eliminating DC–NK contact using transwell membranes.51 Furthermore, not only surface IL-15 but also IL-15Ra is required for NK cell survival, suggesting a role of this complex on NK cell proliferation.51 Finally IL-12, both alone and in synergy with IL-18, is able to induce IFN-c production in DC-activated NK cells and to increase NK cytotoxicity.51,52 Cellular & Molecular Immunology

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Figure 1 The liaison between DCs and NK cells in humans. (a) Mature peripheral DCs12 stimulate peripheral NK cell proliferation, IFN-c production and cytotoxic function via IL-12, IL-18, Type-I IFN, IL-15 secretion and CD40. (b) NK cells induce maturation of immature DCs4 into mDCs. The subsequent production of IL-15, IL-10, IL-18 and IDO by mDCs contributes to tolerance establishment and maintenance of pregnancy. (c) NK cells kill iDCs through NKp30. A balance between activating and inhibitory signals is necessary at the immunological synapse between mDCs and resting NK cells. DC, dendritic cell; iDC, immature dendritic cell; IFN, interferon; mDC, mature dendritic cell; NK, natural killer.

DC-NK cell cross-talk is bidirectional and therefore pNK cells also regulate DCs. In vitro, human pNK cells have been shown to induce DC maturation at high DC/NK cell ratios and to increase DC capacity to release pro-inflammatory cytokines (TNF-a, IL-12 and IL-15) (Figure 1b).49 Additionally, NK cells participate in the up-regulation of antigen presentation molecules (CD80, CD86 and HLA-DR) on DCs.43 This effect depends on cell-to-cell contact between DCs and NK cells and on TNF-a release by NK cells, because both transwell separation and anti-TNF antibodies inhibit this process.49 This activation by human pNK cells also induces membrane IL-15 expression on DCs which, as mentioned previously, is important for NK cell proliferation.53 The activation of human DCs by pNK cells may be important in unique immune situations such as pregnancy, in which pathogen-related molecules or inflammation are not present to drive DC maturation and effective antigen presentation. Finally, pNK cells can also induce or inhibit DC death (Figure 1c) depending on the DC subtype. Human in vitro studies show that a low DC/NK ratio resulted in iDC lysis, requiring the NKp30 receptor.49,54–56 However, DCs are able to protect themselves from NK cell lysis through maturation and acquisition of HLA class I molecules that interact with inhibitory NK cell receptors.57,58 DC–NK cell cross-talk is bidirectional and requires both the synergistic action of several cytokines and cell-to-cell contact. NK/DC LIAISON AT THE FETOMATERNAL INTERFACE DC-SIGN1 DCs and CD561 NK cells are the dominant immune cell populations in human first trimester decidua.5,20,59 The intimate contact between these cells in human decidua was first described using histochemical analysis by Ka¨mmerer and coworkers,5 showing that 52% of DC-SIGN1 cells were in close proximity with at least one NK cell.5 This is in line with our findings in tissue (unpublished data) and in freshly isolated cell suspensions from human decidua using FACS analysis and Cellular & Molecular Immunology

confocal fluorescence microscopy.6 The interaction of these cells at the fetomaternal interface, but not in non-pregnant endometrium, suggests a pregnancy-specific interaction for these cells. However, most studies regarding DC–NK cell interactions have been performed using peripheral cell populations. During normal pregnancy, reciprocal DC–NK cell cross-talk occurs both by cell-to-cell contact and through cytokine secretion (Figure 2). iDCs may play a role in CD561 NK cell recruitment, proliferation and inhibitory receptor expression (Figure 2a) as shown by CD561 NK cell and decidual iDC coculture, demonstrating that only one-third of NK cells proliferated in contact with iDC cells.11 This suggests a selective expansion of NK cells by iDCs that is beneficial for pregnancy outcome. Additionally, NK cells proliferate and increase inhibitory receptor expression in response to iDC-derived IL-15.11 The CD94/NKG2A inhibitory receptor has the ability to bind HLA-E expressed by trophoblast cells, which results in trophoblast protection from NK cytotoxicity.59 It also has been demonstrated that, using cells from spleen51 and blood,53 immature DCs express IL-15Ra on their surfaces and IL15Ra is upregulated in mDCs.51 Indeed, both IL-15 and IL15Ra are required for NK cell survival, suggesting that this IL-15/IL-15Ra complex is needed for NK cell proliferation induced by DCs. These data prompted us to hypothesize that the liaison between NK cells and immature DC-SIGN1 cells might be favored in decidual tissue by the expression of IL15Ra. Moreover, iDCs are able to affect the cytokine profile of dNK cells by inducing the IFN-c release of dNK cells.40 In turn, dNK-derived IFN-c induces the expression of some suppressive molecules, such as indoleamine 2,3-dioxygenase, in decidual DCs, thereby promoting the induction of regulatory T cells in the human decidua (Figure 2b).60 Similarly, dNK cells are also able to influence DC function during pregnancy. dNK cell-derived IL-10 prevents the maturation of iDCs, thus protecting the trophoblast cells against mDC-initiated cytotoxic

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Figure 2 DC and NK cell interactions at the human fetomaternal interface. (a) DC-derived IL-15 and membrane-bound IL-15Ra on immature DCs4,51 activate NK cell recruitment, proliferation and IFN-c production. (b) Activation of DCs induced by NK cells through IFN-c contributes to the induction of regulatory T cells. (c) HLA-G expression on DC-SIGN1 and DC-10 DCs inhibits NK cell cytotoxicity via IL-10 production, thereby contributing to tolerance establishment and maintenance of pregnancy. (d) NK cells can inhibit DC-SIGN1 maturation or induce apoptosis in DCSIGN1 DCs as a mechanism of tolerance to avoid their maturation and migration to the local lymphoid tissues. A balance between activating and inhibitory signals is necessary at the DC–NK cell immunological synapse. DC, dendritic cell; IFN, interferon; NK, natural killer.

T-cell responses.59 Furthermore, IL-10 specifically inhibits decidual DC IL-12 secretion during normal pregnancy regardless of the DC maturation state.13 Thus, IL-10 secretion by decidual NK cells in the decidual microenvironment seems to inhibit the DCs, promoting the optimal Th2-dominant state, which in turn abolishes the NK cell-mediated cytotoxicity on trophoblast cells (Figure 2d). Recently, our group suggested that dNK cells kill DC-SIGN1 DCs in vivo through apoptosis.6 Using cell suspensions isolated from human decidua, we detected the presence of a DC–NK cell conjugate, whereby DC-SIGN1 cells presented a ‘boiling’ morphology, suggesting that CD56bright NK cells had killed the DC-SIGN1 DCs by apoptosis. A possible explanation for this is that NK cells kill DCs as part of a tolerance mechanism that prevents mature DCs from migrating to the lymphoid tissues where they can activate Th1 cells (associated with spontaneous abortion) (Figure 2d). Other mechanisms involved in controlling NK cell-mediated DC lysis during human first trimester pregnancy could be in relation to HLA-G expression (Figure 2c). HLA-G expression on DC-10 tolerogenic decidual DCs,26 and DC-SIGN1 DCs,21 through

the interaction with NK cell receptors (KIRDL4 and ILT2), may inhibit lytic NK cell activity similar to the mechanism by which HLA-G protects trophoblast cells. CD56bright NK cells are important for the maintenance of pregnancy, and the interaction with the HLA-G not only on the trophoblast, but also on DC-10 and DC-SIGN1 DCs could thereby inhibit cytolytic activity and protect the fetus from the maternal immune system. Nevertheless, opposing data have shown that HLA-G activates dNK cells and the production of angiogenic factors that are needed to induce vascular remodeling, an important process for successful implantation and placentation.61 Together, these findings support the notion that, in human decidua, CD561 NK cell/DC-SIGN1 DC liaison might play an important role in modulating the balance between immune response and tolerance. CONCLUDING REMARKS Elucidating the major cell populations involved in tolerance at the fetomaternal interface has been a major focus for pregnancy research. Decades of investigation have illuminated NK cells and DCs as crucial immune cell populations in the progression Cellular & Molecular Immunology

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of a healthy pregnancy. Studying the significance of these DC and NK cells individually and the DC–NK cell liaison in human decidua are crucial to understanding the immunology and the tolerance mechanisms during human pregnancy. CONFLICTS OF INTEREST The authors declare that no conflicts of interest exist. ACKNOWLEDGEMENTS The authors apologize to the many authors whose excellent papers could not be cited in this brief review. ITG received the Charite` Habilitation Fellowship. ELD is supported by a contract from University of Granada (Spain) and RMF is supported by a Sara Borrel contract from Ministry of Economy and Competitiveness (Spain).

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