- Email: [email protected]
Natural killer T cells in Preeclampsia: An updated review
Biomedicine & Pharmacotherapy 95 (2017) 412–418
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha
Review
Natural killer T cells in Preeclampsia: An updated review a,b,d
Vida Hashemi , Sanam Dolati ⁎ Mehdi Yousefic,d,
a,c,d
, Arezoo Hosseini
a,c,d
, Tohid Gharibi
a,c,d
MARK e
, Shahla Danaii ,
a
Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran Department of Basic Science, Faculty of Medicine, Maragheh University of Medical Sciences, Maragheh, Iran Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran d Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran e Gynecology Department, Eastern Azerbaijan ACECR ART Center, Eastern Azerbaijan Branch of ACECR, Tabriz, Iran b c
A R T I C L E I N F O
A B S T R A C T
Keywords: NKT cells Preeclampsia Pregnancy Cytokine
Preeclampsia (PE), as a pregnancy-specific syndrome, has become one of the main causes of maternal and fetal mortality worldwide and is known as a major risk factor for preterm birth. PE is typically characterized by hypertension, significant proteinuria, and an excessive maternal systemic inflammatory response. Recent evidences provide support for the notion that Natural killer T (NKT) cells (a small, but significant immunoregulatory T cell subset of human peripheral blood lymphocytes) play pivotal roles in pregnancy. NKT cells with unique transcriptional and cytokine profiles exist in different peripheral tissues acting as mediators between the innate and adaptive immune systems. NKT cells secrete Interleukin-4 (IL-4) and Interferon-γ (IFN-γ) which might regulate the balance between Type 1 T helper (Th1) and Type 2 T helper (Th2) responses. During pregnancy, maternal immunity is biased towards type II cytokine production to inhibit the function of type I cytokines that could be harmful for the developing fetus. This shift to type II cytokines does not occur in preeclamptic patients. In this review, we discuss the numbers, phenotype, changes, and the functional activity of Natural killer T (NKT) cells during normal pregnancy and preeclampsia.
1. Introduction As a specific disorder, preeclampsia (PE) occurs in the second half of pregnancy [1].The complications and their associated pathologies inherent in PE are known to be as the major causes of maternal and fetal morbidity as well as mortality across the globe [2–4]. For instance, PE is thought to be responsible for preterm birth, intrauterine growth restriction, and prenatal death in the fetus as well as in eclampsia and hemolysis and elevated liver enzymes and low platelet count(HELLP) syndrome in the mother [5]. Approximately 40% of premature births are reported to be delivered before 35 weeks of gestation [2]. Furthermore, preeclampsia is claimed to be the causative factor for nearly 12–25 percent of fetal growth restriction and 15–20 percent of preterm birth cases [6].Within the recent years, the rate of maternal morbidity and mortality associated with preeclampsia has shown a considerable decrease in developed countries [5]. However, there has been reported an increase in later-life death related to cardiovascular diseases, which is independent of other risk factors [2,4]. Moreover, preeclampsia is prevalent in women who experience their first pregnancy or carry twins [7]. High blood pressure
⁎
(≥ 140 mm Hg systolic or ≥ 90 mmHg diastolic on ≥ 2 occasions at least 6 h apart) [8], proteinuria [9], (at least 300 mg per 24 h) [5], and dysfunction of different organs [10] are hallmark characteristics of this clinical syndrome. There are also some risk factors associated with preeclampsia which include nulliparity, multifetal gestations, previous history of preeclampsia, obesity, diabetes mellitus, vascular and connective tissue disorders such as systemic lupus erythematosus and antiphospholipid antibodies syndrome, age > 35 years at first pregnancy, smoking, and African-American race [11]. Recently, it has been found that immune abnormalities make significant contributions to the pathogenesis of preeclampsia [12]. The findings have suggested that innate immunity play a more important role than adaptive immunity in the emergence of preeclampsia, especially increase of circulating monocytes, neutrophils and natural killer (NK) cells [13]. Also, it is of interest to note that there is an exacerbated maternal inflammatory response in patients with preeclampsia [14]. These responses may be attributed to the dominance of Th1 cells [15]. Natural killer T (NKT) cells are recognized as a distinct subset of
Corresponding author at: Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. E-mail addresses: Yousefi[email protected], mehdi_yusefi@yahoo.com (M. Yousefi).
http://dx.doi.org/10.1016/j.biopha.2017.08.077 Received 27 April 2017; Received in revised form 19 August 2017; Accepted 19 August 2017 0753-3322/ © 2017 Elsevier Masson SAS. All rights reserved.
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al.
lineage of iNKT cells known as NKT10 cells [40]. Type II variant NKT cells (VNKT) [28] are defined as CD1d-dependent T lymphocytes that do not express the invariant TCR-α chain and cannot recognize the lipid antigen α-GalCer [41]. VNKT cells are able to express a more diverse range of T-cell receptors (TCRs), and often play roles conflicting or cross-regulatory with iNKT cells [28]. VNKT cells are also more abundant in human than mouse [42]. Here, we focus on Type I NKT cells [43]. iNKT cells can be subdivided into NKT1, NKT2, NKT17, NKTFH, NKT10 regulatory and Foxp3+ iNKT cells [26,44]. The maturation of these cells in mouse consists of several distinct stages on the expression of CD24, CD44 and NK1.1 molecules. The most immature stage of iNKT cells is defined as stage 0 (CD24 high CD44lowNK1.1−) which is followed first by stage 1 (CD24lowCD44lowNK1.1−) and then by stage 2 (CD24lowCD44highNK1.1). Mature iNKT cells (Stage 3) are subdivided into at least three distinct populations, including NKT1 (CD4+/− NK1.1+), NKT2 (CD4+ NK1.1−), and NKT17 (CD4− NK1.1−) [45,46]. NKT1 and NKT2 mainly reside in non-lymphoid organs, while NKT17 cells are found in the peripheral lymph nodes (Fig. 1) [26]. NKT1,when activated, express high levels of T-bet and produce IFNγ [47]. These cells have also been demonstrated to express IL-15Rα (CD122) and loss of IL-15 also resulted in loss of NKT1 cells [48]. However, loss of T-bet or functional IL-15 has been found to enhance the number of NKT2 and NKT17 cells [47,49]. Recent findings have suggested that the transcription factor inhibitor of DNA binding 2(ID2) is highly upregulated in the NKT1 sublineage [50]. NKT2 cells, which are similar to Th2 cells, are characterized based on the cell surface expression of CD4 and interleukin-17 receptor B (IL17RB) [51]. Moreover, these cells are able to produce interleukin-4 (IL4) and interleukin-13 (IL-13). IL-17RB has been shown to be expressed also by NKT17 cells [49]. A new subset of CD4, NK1.1 NKT cells, has been identified which are characterized by their ability to produce very high amounts of IL-17 (NKT-17) early after being activated without the need for polarization [52–54]. NKT-17 cells express retinoic-acid-receptor-related orphan receptor (ROR) γt and Interleukin-23 receptor (IL-23R) [55]. Natural killer T follicular helper (NKTFH) cells trigger specific antibody responses and germinal center reactions (GCs). NKTFH cells containing CD4+,CD44high,programmed cell death protein 1(PD-1+), CX-C chemokine receptor type 5,(CXCR5)+, B-cell lymphoma 6 protein (Bcl6+) and the capacity for IL-21 secretion display high similarities to TFH cells. New findings highlight the significant role of NKTFH cells during antibody responses to protein [56,57], lipid, and carbohydrate antigens [58]. Recently, invariant NKT(iNKT) cells have been found to adopt the phenotype of TFH cells and to be localized within GCs. This finding is consistent with their ability to provide help for cognate B cells. The same procedure is required to differentiate iNKTFH and TFH cells [56] except for the fact that IL-21 is not needed for iNKTFH cell formation, even though it is crucial to their cognate functions [59]. NKT10 regulatory cells have a new surface phenotype and are able to produce a different cytokine pattern such as production of IL-10, a cytokine which mediates immune suppression. This capacity of NKT10 regulatory cells has served as a basis for suggesting the name “induced NKT10 cells”. In addition, FOXP3 is required for the proper functioning of regulatory T cells (Tregs) [60]. Moreover, the expression of this transcription factor can be induced in iNKT cells [61,62]. However, NKT10 cells do not induce FOXP3 [63]. NKT10 cells possess some properties of regulatory T cells including the increased expression of cytotoxic T-lymphocyte associated protein 4 (CTLA4), neuropilin1(Nrp1), and folate receptor 4 (FR4) [64]. Understanding the function of NKT10 subset may lead to obtaining deep insights into the anti-inflammatory role of iNKT cells in a variety of disease settings. It has been revealed that high expression levels of IL-10 mRNA are related to the
peripheral leukocytes [3]. Once activated, NKT cells secrete cytokines and boost the immune response which is triggered by a variety of interactions between NKT cells and other cell types including conventional CD4+ T and CD8+ T cells, dendritic cells (DCs), Natural killer (NK) cells, B cells, T regulatory (Treg) cells, macrophages and neutrophils [16]. These cells impact on large variety of immunological responses which include autoimmunity [17], antimicrobial host responses [18], resistance to tumors and transplantation immunity [19]. that are also increasingly activated in PE [3]. Some studies have provided supporting evidence for the possible significant role of NKT cells in pregnancy and preeclampsia. Consistent with this, it has been reported that treatment of pregnant mice with αGalactosylceramide (α-GalCer) leads to the occurrence of abortion which might be attributed to the release of Interferon gamma (IFN-γ) by NKT cells [20,21]. Also, there are some convincing data highlighting a strong link between NKT cells and priming Type 2 T helper (Th2) immune responses [22]. Furthermore, it has been demonstrated that both NK cells and proliferating cells, which are crucial to the progression and success of pregnancy, are regulated by NKT cells [23]. Based on these facts which imply the importance of NKT cells in the emergence of preeclampsia, the current review aims to investigate the roles that NKT cells play in the pathogenesis of this condition. 2. Natural killer T subsets NKT cells, which were first described in the late 1980s as innate-like lymphocytes [24] are known to be a new lymphocyte lineage [25]. These cells are characterized by the presence of Natural killer cells (NK cells) receptors with an invariant α-chain, NKT cells express αβTCR [26]. NKT cells are representative of a group of T lineage cells of thymic origin which have a variety of features. These features can be used to describe how NKT cells are different from ‘conventional T cells’ [26,27]. NKT cells recognize lipid antigens (mainly glycolipids) in the context of CD1d, a non-polymorphic major histocompatibility complex (MHC) class I-like molecule [27]. CD1d is expressed by hematopoietic cells [28] and on the surface of villous or extravillous trophoblasts [29] to interact with NKT cells in the deciduas [30]. The amion and the placenta are riched for sphingoglycolipids, many of which are gangliosides-containing sialic acid [31] that perhaps presented in the context of CD1d and recognized by NKT cells [32]. So it is vital to explain the roles of NKT cells-restricted CD1 that reside at the feto-maternal interface during pregnancy [33]. NKT cells are used to name some subsets of T lymphocytes, which are distinct in their phenotype, functional capacities and tissue distribution. There are two distinct types of NKT cell subpopulations [34] known as Type I and Type II lymphocytes [35]. NKT cells develop in the thymus, at least for the invariant NKT (iNKT) cells (Type I) cell lineage. There are numerous lines of convincing evidence highlighting that these cells undergo positive and negative selections [28]. Type I iNKT cells comprise a small, but significant immunoregulatory T-cell subset [29]. These cells express canonical TCRα chains which consist of certain gene segments, Vα14-Jα18 in mouse and Vα24-Jα18 in human. Furthermore, they preferentially pair with specific TCRβ chains including Vβ8, Vβ7, or Vβ2 in mouse and Vβ11 in human [24]. The majority of decidual NKT cells as well as other tissues such as bone marrow and liver and peripheral blood in human express Vβ11 [36]. iNKT cells are capable of recognizing a spectrum of bacteria-derived lipids. In addition, iNKT cells can also recognize endogenous lipids [37]. This property provides them with the ability to mature DCs and B cells in a CD40-dependent manner [38]. iNKT cells are able to quickly release both Th1-type and Th2-type cytokines (IFN-γ, TNF-α, IL-10 and IL-4) [39] in response to α-Galactosylceramide (α-GalCer). αGalCer is also thought to have the capacity for inducing a distinct 413
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al.
Fig. 1. NKT cell Subpopulations: NKT cells are representative of a group of T lineage cells of thymic origin which have a variety of features. They recognize lipid antigens (mainly glycolipids) in the context of CD1d, a non-polymorphic major histocompatibility complex (MHC) class I-like molecule, NKT cells are distinct in their phenotype, functional capacities and tissue distribution. There are two distinct types of NKT cell subpopulations known as iNKT cells (Type I) and VNKT cells (Type II). VNKT cell do not express the invariant TCR-α chain and cannot recognize the lipid antigen α-GalCer, also able to express a more diverse range of TCRs, and often play roles conflicting or cross-regulatory with iNKT cells. iNKT cells comprise a small, but significant, immunoregulatory T-cell subset, These cells are able to quickly release both Th1- type and Th2- type cytokines in response to α-Galactosylceramide (α-GalCer). As well as iNKT cells can be subdivided into at least 6 distinct from iNKT precursor cells in mouse. This categorization is performed based on the expression of CD24, CD44 and NK1.1 molecules. Each terminally differentiated lineage is defined by expression of a unique selection of cytokines and transcription factors. NKT1 cells express high levels of Tbet and release IFN γ and some IL-4 upon activation as well as express CD122, NK1.1. NKT2 cells continually express Gata3, CD4 and predominantly release IL-4 and IL-13 upon activation. NKT17 cells express ROR γt, IL-23R, CD4 and release IL-17 upon activation. NKTFH express the transcription factor Bcl6, CXCR5 and develop after activation although it also releases IL-21. NKT10 cells, although, these cells can be defined by IL-10 production as well as expression of NRP-1,FR4 and PD1. F0XP3 NKT cells express FOXP3, GITR, CTLA-4 and PLZF also release TGF-β.
than in peripheral blood (10 times) [29,68]. The iNKT cells present in the decidual tissue are involved in the maintenance of pregnancy in both humans and mice. NKT cells (CD3+/CD161 + ) might control the balance of Th1/Th2 at the maternal-fetal interface [68]. Also, the role of NKT cells in abortions is complicated [69]. NKT cells express not only T cell marker (CD3) but also NK cell markers [70] such as NK1.1 in mice (CD161 in human) [71]. Furthermore, CD161(is a C-type lectin receptor) which activates NK cell cytotoxicity [72]. In general, murine NKT cells carry an antigen has been recently characterized as CD49b, it is a 150 kD integrin α chain also known as α2 integrin(DX5) [3–5],also these cells express lectin-like type II transmembrane disulfide-bonded homodimer expressed on natural killer (NK) cells and some T-cell subsets(Ly-49) receptors, NKG2 (family Ctype lectin) receptors, and CD94 [24]. Human NKT cells often express surface molecules including CD56 [24,27], CD161 [27,35], CD94 and natural killer group 2D (NKG2D), NKG2A, CD16, and CD69 [71]. Although CD8+ NKT cells are found in human, they are rare in mouse. Recently, some reports have described phenotypic differences between CD4+ and CD4− iNKT cell subsets [73]. While the primary function of CD4− iNKT cells seems to be the secretion of Th1-type cytokines such as interferon gamma (IFN- γ) and tumor necrosis factorα (TNF-α). CD4+iNKT cells have been reported to be capable of producing both Th1-type and Th2-type cytokines. [29].
post-activated host iNKT cells. This observation may provide the possibility of early research on the NKT10 sublineage [65]. Several lines of evidence have indicated that, in certain settings, iNKT cells could be induced to express Foxp3 [61,62]. Foxp3+ iNKT cells indicate the phenotypic hallmarks of Treg cells including the expression of CD25, glucocorticoid-induced TNFR (GITR), and CTLA-4; while, they retain NKT cell-specific characteristics such as promyelocytic leukaemia zinc finger protein (PLZF) expression [62]. Both human and mouse-derived iNKT cells stimulated in vitro by transforming growth factor beta 1 (TGF-β) may be induced to express Foxp3. However, human-derived Foxp3+ iNKT cells, when generated in vitro in the presence of both TGF-β and rapamycin, could only suppress the proliferation of conventional T cells [61].
3. NKT cell numbers and phenotype during normal pregnancy and preeclampsia NKT producers of regulatory cytokines involved in controlling ovulation [66]. In mouse, NKT cell population comprises nearly 1% of peripheral lymphocytes. Moreover, the number of NKT cells in the peripheral blood mononuclear cells of human tends to be even less than mouse ranging from 0.01% to 1% [26]. As a minor population in the peripheral blood, peripheral NKT cells may have less significance during the reproductive process [67]. The other point is that NKT cells have larger numbers in the decidua 414
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al.
CD3+CD56+ cells can be divided into two subsets: CD3+CD56+CD16− and CD3+CD56+CD16+ [74]. Among these, CD3+CD56+CD16− subset might be harmful to fetal tolerance. In line with this, the increased numbers of CD3+CD56+CD16− NKT cell subset have been indicated to correlate with post-implantation pregnancy loss [75]. However, these two cell subsets display remarkable differences. Southcombe et al. compared the number and phenotype of iNKT cells in preeclamptic and normal pregnant women and found that these two groups have no discrepancy between the number of NKT cells per mL of blood and the percentage of iNKT cells. Also, there was no change observed in the proportion of iNKT cells expressing CD4 or CD8 markers as well as in the expression of the early activation marker CD69 by iNKT cells. Moreover, normal pregnant women indicated a slight decrease in the number of iNKT cells producing IFN-γ compared with preeclamptic women [76]. Another study reported that the increased number of NKT cells in blood may lead to recurrent pregnancy loss (RPL) [66]. It has been shown in the mouse that Vα14 NKT cell population is stimulated by a CD1d-restricted ligand and α-Galactosylceramide (α-GalCer) to produce type-I cytokines resulting in occult pregnancy loss and a homologous population of NKT cells (CD3+CD161+Vα24+), recognizing the same ligand, has been identified in humans [77]. Also, the ratio of peripheral blood NKT1/NKT2 cells seems to be higher in preeclamptic women than normal pregnant ones [69]. Previously, it has been indicated that NKT cell numbers are reduced in the decidua of women with recurrent miscarriages [78]. Borzychowski et al. reported significantly decreased NKT1⁄NKT2 cell ratios in normal pregnancy compared with pre-eclamptic women [79]. Boyson and et al. found the accumulation of IFN-γ-producing iNKT cells in the decidua of normal pregnant women, while their peripheral blood CD4+ iNKT cells exhibited a Th2 profile (IL-4, IL-5, IL-6, IL-10) [29]. Moreover, it has been reported that the expression of CD95 on the iNKT cells of healthy pregnant women is significantly higher than iNKT cells derived from preeclamptic patients [15]. In preeclamptic patients, the percentage of potential cytotoxic perforin expression by iNKT cells is significantly elevated compared with normal women. Furthermore, the number of iNKT cells co-expressing NKG2A and NKG2D receptors is significantly lower in preeclamptic patients than normal women [15].
Moreover, the activation of human antigen-presenting cells (APCs) by toll-like receptor (TLR) ligands modulates the lipid biosynthetic pathway. This process results in enhanced recognition of lipids by iNKT cells, which are certified by IFN- γ secretion and elevates the rate of CD1d-restricted iNKT cell activation [19]. In first trimester extravillous trophoblasts cells express CD1d and probably interact with maternal iNKT cells for normal placentation and implantation [15]. The pathophysiology of preeclampsia is recognized initial at pregnancy, where increased decidual iNKT activity can lead to poor trophoblasts invasion of the spiral arteries and placental insufficiency, even though later events comprise a systemic inflammatory response [15]. Invariant NKT cells in 3rd trimester peripheral blood of women with preeclampsia show a Th1 phenotype and therefore might take an active part in creating a systemic inflammatory dysfunction. Newly, Borzychowski et al. showed meaningfully reduced NKT1 > ⁄NKT2 cell ratios in normal pregnancy compared with nonpregnant and preeclamptic women [79]. On iNKT cells of preeclamptic patients, there is a changed balance of NK cell activating and inhibitory receptors. In preeclamptic women iNKT cells have a poorer chance to transduce inhibitory signals than those of healthy pregnant women. Peripheral Vα24 iNKT cells of preeclamptic women exhibited a Th1 dominant profile. The percentage of activated iNKT cells in preeclamptic women was expressively higher, and the same cells secreted more IFN-γ, contained more perforin, and exposed a decreased apoptotic potential compared to normal pregnancy [15]. In preeclampsia iNKT cells are activated, which may, be due to the altered expression of the NK cell inhibitory and activating receptor repertoire of the cells. Furthermore, because of their reduced apoptotic potential, these activated cytotoxic cells could be longer lived than those in normal pregnancy [86]. Therefore, iNKT cells at the materno-fetal interface may be activated by self-lipid antigens versus soluble factors from APCs upon TLR signaling, and play a role in inflammation-induced preterm birth. Also, TLR4 is responsible for LPS-induced preterm birth [87]. In normal pregnancy, Boyson et al. established the accumulation of IFN-γ producing iNKT cells in the decidua, while peripheral blood CD4+ iNKT cells displayed a Th2 profile [69,88]. 2 A successful pregnancy depends on stimulating the production of Th2-type cytokines and inhibiting the production of Th1-type proinflammatory cytokines [89]. Th1 responses in human pregnancy may be suppressed via down-regulating the expression of nuclear factor κB (NFκB) and T-box transcription factor(T-bet) [90]. The anti-inflammatory mediators produced by Th2 cells, including IL-4, IL-10 and TGFβ, appear to be needed for the maintenance of pregnancy due to their immunosuppressive effects. By contrast, proinflammatory mediators secreted by Th1 cells, such as TNFα, IFN-γ and monocyte chemoattractant protein-1(MCP-1), act to cause abortion or preeclampsia [71]. (Table 1). 4 NKT cells may play important roles in the success of implantation and fetal tolerance. It is commonly believed that the adequate function
4. NKT cell function in normal pregnancy and PE There are numerous reports in the literature highlighting the importance of NKT cells in human pregnancy. As mentioned before, NKT cells produce both Th1-type (IFN- γ) and Th2-type (IL-4) cytokines and control the function of T-helper cells (Th cells) at the materno-fetal interface [68]. Furthermore, the activities of NKT cells that result in cytotoxic effects are mediated by perforin/granzyme B and Fas ligand. It is interesting that functional molecules are used differentially by NKT cells under different circumstances [25]. TGF-β, TNF-α IFN- γ, IL-2, IL4, and IL-17 are pro- and anti-inflammatory cytokines which can be generated by activated NKT cells. It has been reported that mature IL-12 induced NKT cells can secrete type-1 cytokines [80]. NKT cells secrete IL-4 and IFN-γ cytokines which might be involved in regulating Th1/Th2 balance in the endometrial tissue [81]. At the feto-maternal interface [82], in pregnancy and in preeclampsia [83], this process is crucial to the immunological success of pregnancy. Th1 cells predominate the nonpregnant endometrium, especially during the proliferative phase; while Th2 cells predominate decidua in early pregnancy [84]. Th1 dominance seems to be associated with reproductive failures in preeclampsia; however, it has been reported that peripheral blood mononuclear cells show decreased IL-10 and increased IL-2 and IFN- γ production during spontaneous abortions [85]. Abortion occurs when NKT cells are activated by αGal-Cer [68].
Table 1 Profile of NKT cell-produced cytokines in preeclampsia and normal pregnancy. Preeclampsia
Normal pregnancy
TNF-ɑ IL-18 IL-12 MCP-1 IL-18R IL12P70 IFn- γ
IL-4 IL-10 TGF-β ST2L(IL1R)
There is a shift toward Th1-type cytokines in preeclampsia with increased proinflammatory cytokines, but toward Th2-type cytokines in normal pregnancy.
415
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al.
5. Changes in peripheral NKT cell populations in normal pregnancy and PE
of cytokine network is of particular importance for maintaining pregnancy. This finding is consistent with “immunothrophic hypothesis” which postulates that during the physiological pregnancy, the balance of Th1/Th2 activity strongly shifts toward Th2 activity. Therefore, Th1 activity is incompatible with a successful pregnancy [71]. In preeclampsia, the bias is toward type 1 immunity which is similar to nonpregnant women [79]. 6 There are two stable and universal surface markers for type-1 and type-2 subsets [91]. IL-18 receptor (IL-18R) is selectively expressed on type 1 lymphocyte lineages and stimulation expressed gene 2 a membrane-bound receptor (ST2L), a homologue of IL-1R, is selectively expressed on type 2 lymphocyte lineages in mouse and human[91,92]. Both ST2L and IL-18R are members of the TLR superfamily. In addition, IL-18 induces IFN-γ production from Th1 and NK cells [93]. These changes in the proportion of iNKT cells may be crucial for the maintenance of an adequate cytokine balance, which is necessary for a successful pregnancy [94]. The elevated serum levels of TNF-α [95], and IL-18 have been reported in preeclampsia (especially in HELLP syndrome) [96]. IL-18 is a cytokine which induces IFN-γ production and diverts Th1 predominant immunity in the presence of IL-12 [97]. The level of the Th2-type cytokine, IL-4, is the same between preeclamptic cases and normal pregnancy subjects in unstimulated peripheral blood mononuclear cell (PBMCs); however, the level of IL-4, stimulated by phytohemagglutiuin (PHA), is significantly lower in preeclamptic patients compared with normal pregnant women [98]. It seems that the balance of Th1-type to Th2-type cytokines shifts to Th1type immunity in preeclampsia [99]. These above findings suggest that Th1 type immunity is present in preeclampsia that the population of Th1 type cells increased, while Th2 type cells decreased in preeclampsia compared to those in healthy pregnancy(Fig. 2) [100] reported that there is a shift to the Type 1 bias of state in preeclampsia with increased proinflammatory circulating cytokines, such as IFN-γ, IL-12P70 and IL-18 [101].
The ability of iNKT cells to drive and modulate immune responses makes them ideal candidates for regulating immunity during pregnancy [67]. Of note, the population of uterine NKT cells is enriched after ovulation and during pregnancy[68]. Although the number of iNKT cells in blood remains constant throughout pregnancy, a slight decrease in CD69 expression on total iNKT cell population has been observed in the third trimester[76]. Peripheral blood leukocytes from normal pregnant woman are primed to produce higher levels of pro-inflammatory cytokines (IL-12, TNF-α, and IL-18) than those from nonpregnant women. However, IFNγ production is suppressed in normal pregnant women[102]. By contrast, it has been reported that although the levels of IL-12 and TNF-α production by peripheral blood leukocytes in preeclampsia are similar to those detected in normal pregnancy, IFN-γ levels shows significantly increased in preeclamptic individuals. Despite elevated cellular production of IL-18 in preeclampsia, this does not seem to be reflected in maternal plasma levels [103]. IL-18 alone can act as a Th2 cytokine. However, in the presence of IL-12, this cytokine functions synergistically to induce Th1 responses. It has also been found that a high ratio of IL-18 to IL-12 can result in shift toward Th2 responses during normal pregnancy, whereas a low ratio of IL-18 to IL-12 may account for Th1 bias and particularly increased levels of IFNγ production in preeclampsia [104].Thus, defining events seem to focus around IFN-γ production influenced by changes in IL-12 and IL-18 levels during pregnancy and preeclampsia. This question comes up as the source and stimulus of this cytokine production[105]. It has been demonstrated that treatment of pregnant mice with α-GalCer can lead to iNKT-mediated abortion. Several other observations have highlighted the fact that iNKT cells may play key roles in IFN-γ release during pregnancy and preeclampsia [20]. Furthermore, there is evidence indicating that iNKT cells are involved in priming Th2 immune responses [106]. iNKT cells have also been indicated to account for the activation and proliferation of NK cells which are known to be critical for the progression and success of Fig. 2. NKT cells in Pregnancy: Natural killer T (NKT (cells (a small, but significant immunoregulatory T cell subset of human peripheral blood lymphocytes) play pivotal roles in pregnancy. NKT cells with unique transcriptional and cytokine profiles exist in different peripheral tissues acting as mediators between the innate and adaptive immune systems. These cells secrete IL-4 and IFN-γ which might regulate the balance between Type Th1/Th2 responses. During Normal pregnancy, maternal immunity is biased towards type II cytokine (IL-4, TGF-β, IL-10) production to inhibit the function of type I cytokines (IL-12, IFN-γ, TNF-α, IL-18) that could be harmful for the developing fetus. This shift to type I cytokines with increased proinflammatory circulating cytokines occur in preeclamptic patients.
416
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al.
Immunol. 2 (8) (2002) 557–568. [22] N. Singh, et al., Cutting edge: activation of NK T cells by CD1d and α-galactosylceramide directs conventional T cells to the acquisition of a Th2 phenotype, J. Immunol. 163 (5) (1999) 2373–2377. [23] G. Eberl, H.R. MacDonald, Selective induction of NK cell proliferation and cytotoxicity by activated NKT cells, Eur. J. Immunol. 30 (4) (2000) 985–992. [24] J.B. Altman, et al., Antitumor responses of invariant natural killer t cells, J. Immunol. Res. (2015) 2015. [25] M. Taniguchi, T. Nakayama, Recognition and function of V (14 NKT cells, Semin. Immunol. (2000) (Elsevier). [26] A.M. Birkholz, M. Kronenberg, Antigen specificity of invariant natural killer Tcells, Biomed. J. 38 (6) (2015) 470–483. [27] V. Kumar, NKT-cell subsets: promoters and protectors in inflammatory liver disease, J. Hepatol. 59 (3) (2013) 618–620. [28] L. Van Kaer, V.V. Parekh, L. Wu, Invariant natural killer T cells: bridging innate and adaptive immunity, Cell Tissue Res. 343 (1) (2011) 43–55. [29] J.E. Boyson, et al., CD1d and invariant NKT cells at the human maternal?fetal interface, Proceedings of the National Academy of Sciences 99 (21) (2002) 13741–13746. [30] S. Shimada, et al., No difference in natural killer or natural killer T-cell population, but aberrant T-helper cell population in the endometrium of women with repeated miscarriage, Hum. Reprod. 19 (4) (2004) 1018–1024. [31] R. Rueda, K. Tabsh, S. Ladisch, Detection of complex gangliosides in human amniotic fluid, FEBS Lett. 328 (1–2) (1993) 13–16. [32] D.Y. Wu, et al., Cross-presentation of disialoganglioside GD3 to natural killer T cells, J. Exp. Med. 198 (1) (2003) 173–181. [33] T. Kawano, et al., CD1d-restricted and TCR-mediated activation of V(14 NKT cells by glycosylceramides, Science 278 (5343) (1997) 1626–1629. [34] E. Peralbo, C. Alonso, R. Solana, Invariant NKT and NKT-like lymphocytes: two different T cell subsets that are differentially affected by ageing, Exp. Gerontol. 42 (8) (2007) 703–708. [35] W.L. Chan, et al., NKT cell subsets in infection and inflammation, Immunol. Lett. 85 (2) (2003) 159–163. [36] C. Couedel, et al., Diverse CD1d-restricted reactivity patterns of human T cells bearing invariant AV24BV11 TCR, Eur. J. Immunol. 28 (12) (1998) 4391–4397. [37] A.P. Lawton, et al., The mouse CD1d cytoplasmic tail mediates CD1d trafficking and antigen presentation by adaptor protein 3-dependent and-independent mechanisms, J. Immunol. 174 (6) (2005) 3179–3186. [38] I.F. Hermans, et al., NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells, J. Immunol. 171 (10) (2003) 5140–5147. [39] G. Galli, et al., CD1d-restricted help to B cells by human invariant natural killer T lymphocytes, J. Exp. Med. 197 (8) (2003) 1051–1057. [40] P.J. Brennan, M. Brigl, M.B. Brenner, Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions, Nat. Rev. Immunol. 13 (2) (2013) 101–117. [41] S. Stankovic, et al., Distinct roles in NKT cell maturation and function for the different transcription factors in the classical NF-κB pathway, Immunol. Cell Biol. 89 (2) (2011) 294–303. [42] P. Arrenberg, I. Maricic, V. Kumar, Sulfatide-mediated activation of type II natural killer T cells prevents hepatic ischemic reperfusion injury in mice, Gastroenterology 140 (2) (2011) 646–655. [43] D.I. Godfrey, et al., NKT cells: what's in a name? Nat. Rev. Immunol. 4 (3) (2004) 231–237. [44] H.M. Buechel, M.H. Stradner, L.M. D’Cruz, Stages versus subsets: invariant natural killer T cell lineage differentiation, Cytokine 72 (2) (2015) 204–209. [45] R. Das, D.B. Sant’Angelo, K.E. Nichols, Transcriptional control of invariant NKT cell development, Immunol. Rev. 238 (1) (2010) 195–215. [46] E.Y. Kim, et al., The transcriptional programs of iNKT cells, Semin. Immunol. 27 (1) (2015) 26–32 (Elsevier). [47] Y.J. Lee, et al., Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells, Nat. Immunol. 14 (11) (2013) 1146–1154. [48] J.L. Matsuda, et al., Homeostasis of V(14i NKT cells, Nat. Immunol. 3 (10) (2002) 966–974. [49] H.et al. Watarai, Development and function of invariant natural killer t cells producing TH 2-and TH 17-Cytokines, PLoS Biol. 10 (2) (2012) e1001255. [50] L.M. D’, et al., E and Id proteins influence invariant NKT cell sublineage differentiation and proliferation, J. Immunol. 192 (5) (2014) 2227–2236. [51] A. Terashima, et al., A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity, J. Exp. Med. 205 (12) (2008) 2727–2733. [52] J.M. Coquet, et al., Diverse cytokine production by NKT cell subsets and identification of an IL-17?producing CD4- NK1. 1- NKT cell population, Proceedings of the National Academy of Sciences 105 (32) (2008) 11287–11292. [53] M.-L. Michel, et al., Identification of an IL-17?producing NK1. 1neg iNKT cell population involved in airway neutrophilia, J. Exp. Med. 204 (5) (2007) 995–1001. [54] R.R. Caspi, et al., NKT cells constitutively express IL-23 receptor and RORγt, and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion, FASEB J. 22 (Suppl. 1) (2008) (1069. 5-1069.5). [55] S. Stankovic, Distinct roles in NKT cell maturation and function for the different transcription factors in the classical NF-[kappa] B pathway, Immunol. Cell Biol. 89 (2) (2011) 294. [56] P.-P. Chang, et al., Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses, Nat. Immunol. 13 (1) (2012) 35–43.
pregnancy [107]. 6. Conclusion In the current article, we made effort to provide an overview of the roles played by NKT cells in preeclampsia. Numerous reports investigating the biological roles of NKT cells have highlighted the fact that these cells hold major roles in innate immunity. Different studies have shown that the number of these cells in decidua is higher than peripheral blood. In preeclampsia, the ratio of Th1-type to Th2-type cytokines shifts toward Th1-type immunity. A large body of evidence provides support for the notion that NKT cell numbers are significantly reduced in normal pregnancy compared with preeclampsia. However, no remarkable discrepancy has been observed in the iNKT cell number or phenotype between normal pregnancy and preeclampsia, even though normal pregnant women show a slight decrease in iNKT cell-secreted IFN-γ compared with preeclamptic patients. Overall, current findings lead to the postulation that when NKT subsets are preferentially induced, they are likely to contribute to preeclampsia. These data also highlight the role of NKT cells in regulating the Th1/Th2 balance as one of the essential functions of these cells in vivo. Both in decidua and peripheral blood, NKT cells are capable of modulating immune response through production of cytokines associated with Th1 (IFN- γ) and Th2 (IL-4, IL-10) cells. There is an imbalance between Th1 and Th2 responses in preeclamptic individuals and these patients show a predominant Th1-type immunity. References [1] S.J. Germain, et al., Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles, J. Immunol. 178 (9) (2007) 5949–5956. [2] A. Perez-Sepulveda, et al., Innate immune system and preeclampsia, Immune Interact. During Reprod. Cycle 5 (244) (2015) 130. [3] H. Ahn, et al., Immunologic characteristics of preeclampsia, a comprehensive review, Am. J. Reprod. Immunol. 65 (4) (2011) 377–394. [4] F.J. Valenzuela, et al., Pathogenesis of preeclampsia: the genetic component, J. Pregnancy 2012 (2011). [5] N. Hariharan, A. Shoemaker, S. Wagner, Pathophysiology of hypertension in preeclampsia, Microvasc. Res. 109 (2016) 34. [6] A. Jeyabalan, Epidemiology of preeclampsia: impact of obesity, Nutr. Rev. 71 (suppl. 1) (2013) S18–S25. [7] N. Al-Jameil, et al., A brief overview of preeclampsia, J. Clin. Med. Res. 6 (1) (2013) 1–7. [8] A. Molvarec, et al., Increased prevalence of peripheral blood granulysin-producing cytotoxic T lymphocytes in preeclampsia, J. Reprod. Immunol. 91 (1) (2011) 56–63. [9] I. Sargent, A. Borzychowski, C. Redman, NK cells and pre-eclampsia, J. Reprod. Immunol. 76 (1) (2007) 40–44. [10] S.I. Gilani, Preeclampsia and extracellular vesicles, Curr. Hypertens. Rep. 18 (9) (2016) 68. [11] E. Eiland, C.M. Nzerue Faulkner, Preeclampsia, J. Pregnancy 2012 (2012). [12] F. Liu, et al., Role of agonistic autoantibodies against type-1 angiotensin II receptor in the pathogenesis of retinopathy in preeclampsia, Sci. Rep. (2016) 6. [13] C.E. Leik, S.W. Walsh, Neutrophils infiltrate resistance-sized vessels of subcutaneous fat in women with preeclampsia, Hypertension 44 (1) (2004) 72–77. [14] J. Bueno-Sánchez, et al., Cytokine production by non-stimulated peripheral blood NK cells and lymphocytes in early-onset severe pre-eclampsia without HELLP, J. Reprod. Immunol. 97 (2) (2013) 223–231. [15] E. Miko, et al., The role of invariant NKT cells in Pre‐Eclampsia, Am. J. Reprod. Immunol. 60 (2) (2008) 118–126. [16] J.L. Matsuda, et al., CD1d-restricted iNKT cells: the ‘Swiss-Army knife’of the immune system, Curr. Opin. Immunol. 20 (3) (2008) 358–368. [17] A. Teige, et al., CD1d-dependent NKT cells play a protective role in acute and chronic arthritis models by ameliorating antigen-specific Th1 responses, J. Immunol. 185 (1) (2010) 345–356. [18] M. Emoto, et al., α-galactosylceramide promotes killing of Listeria monocytogenes within the macrophage phagosome through invariant NKT-cell activation, Infect. Immun. 78 (6) (2010) 2667–2676. [19] L.-P. Li, et al., Depletion of invariant NKT cells reduces inflammation-induced preterm delivery in mice, J. Immunol. 188 (9) (2012) 4681–4689. [20] J.E. Boyson, et al., Gestation stage-dependent mechanisms of invariant natural killer T cell-mediated pregnancy loss, Proc. Natl. Acad. Sci. U. S. A. 103 (12) (2006) 4580–4585. [21] M. Kronenberg, L. Gapin, The unconventional lifestyle of NKT cells, Nat. Rev.
417
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al. [57] I.L. King, et al., Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner, Nat. Immunol. 13 (1) (2012) 44–50. [58] P. Rampuria, M.L. Lang, CD1d-dependent expansion of NKT follicular helper cells in vivo and in vitro is a product of cellular proliferation and differentiation, Int. Immunol. (2015) dxv007. [59] P. Dellabona, S. Abrignani, G. Casorati, iNKT-cell help to B cells: a cooperative job between innate and adaptive immune responses, Eur. J. Immunol. 44 (8) (2014) 2230–2237. [60] S. Sakaguchi, Regulatory T cells: history and perspective, Regul. T cells: Methods Protoc. (2011) 3–17. [61] L. Moreira-Teixeira, et al., Rapamycin combined with TGF-(converts human invariant NKT Cells into suppressive Foxp3+ regulatory cells, J. Immunol. 188 (2) (2012) 624–631. [62] M. Monteiro, et al., Identification of regulatory Foxp3+ invariant NKT cells induced by TGF-β, J. Immunol. 185 (4) (2010) 2157–2163. [63] D. Sag, et al., IL-10?producing NKT10 cells are a distinct regulatory invariant NKT cell subset, J. Clin. Invest. 124 (9) (2014) 3725–3740. [64] L. Fox, S. Hegde, J.E. Gumperz, Natural killer T cells: innate lymphocytes positioned as a bridge between acute and chronic inflammation? Microbes Infect. 12 (14) (2010) 1125–1133. [65] K. Oh, et al., Direct regulatory role of NKT cells in allogeneic graft survival is dependent on the quantitative strength of antigenicity, J. Immunol. 174 (4) (2005) 2030–2036. [66] J. Křížan, et al., Altered distribution of NK and NKT cells in follicular fluid is associated with IVF outcome, J. Reprod. Immunol. 82 (1) (2009) 84–88. [67] S. Shimada, et al., No difference in natural-killer-T cell population, but Th2/Tc2 predominance in peripheral blood of recurrent aborters, Am. J. Reprod. Immunol. 50 (4) (2003) 334–339. [68] H. Tsuda, et al., Characterization of NKT cells in human peripheral blood and decidual lymphocytes, Am. J. Reprod. Immunol. 45 (5) (2001) 295–302. [69] K. Ito, et al., Involvement of decidual Vα14 NKT cells in abortion, Proc. Natl. Acad. Sci. 97 (2) (2000) 740–744. [70] E.I. Ntrivalas, et al., Expression of killer immunoglobulin-like receptors on peripheral blood NK cell subsets of women with recurrent spontaneous abortions or implantation failures, Am. J. Reprod. Immunol. 53 (5) (2005) 215–221. [71] J. Zhou, et al., High circulating CD3+ CD56+ CD16+ natural killer-like T cell levels predict a better IVF treatment outcome, J. Reprod. Immunol. 97 (2) (2013) 197–203. [72] J.C. Ryan, et al., NKR-P1A is a target-specific receptor that activates natural killer cell cytotoxicity, J. Exp. Med. 181 (5) (1995) 1911–1915. [73] P.T. Lee, et al., Distinct functional lineages of human V(24 natural killer T cells, J. Exp. Med. 195 (5) (2002) 637–641. [74] M.J. Van Den Heuvel, et al., Decline in number of elevated blood CD3+ CD56+ NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy, Am. J. Reprod. Immunol. 58 (5) (2007) 447–459. [75] G. Hodge, et al., Increased natural killer T-like cells are a major source of proinflammatory cytokines and granzymes in lung transplant recipients, Respirology 17 (1) (2012) 155–163. [76] J. Southcombe, C. Redman, I. Sargent, Peripheral blood invariant natural killer T cells throughout pregnancy and in preeclamptic women, J. Reprod. Immunol. 87 (1) (2010) 52–59. [77] R.M. Gorczynski, et al., The same immunoregulatory molecules contribute to successful pregnancy and transplantation, Am. J. Reprod. Immunol. 48 (1) (2002) 18–26. [78] T. Yamamoto, et al., Proportion of CD56+ 3+ T cells in decidual and peripheral lymphocytes of normal pregnancy and spontaneous abortion with and without history of recurrent abortion, Am. J. Reprod. Immunol. 42 (6) (1999) 355–360. [79] A.M. Borzychowski, et al., Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells, Eur. J. Immunol. 35 (10) (2005) 3054–3063. [80] M.J. Loza, L.S. Metelitsa, B. Perussia, NKT and T cells: coordinate regulation of NK-like phenotype and cytokine production, Eur. J. Immunol. 32 (12) (2002) 3453–3462. [81] H. Chen, W.E. Paul, Cultured NK1. 1+ CD4+ T cells produce large amounts of IL4 and IFN-gamma upon activation by anti-CD3 or CD1, J. Immunol. 159 (5) (1997) 2240–2249. [82] R. Geiben-Lynn, et al., Non-classical natural killer t cells modulate plasmid DNA
[83] [84]
[85]
[86] [87] [88] [89] [90] [91]
[92] [93] [94]
[95]
[96]
[97] [98] [99]
[100]
[101]
[102]
[103] [104]
[105] [106]
[107]
418
vaccine antigen expression and vaccine-elicited immune responses by MCP-1 secretion after interaction with a (2-Microglobulin-independent CD1d, J. Biol. Chem. 284 (49) (2009) 33800–33806. S. Hori, T. Nomura, S. Sakaguchi, Control of regulatory T cell development by the transcription factor Foxp3, Science 299 (5609) (2003) 1057–1061. S. Saito, et al., Distribution of Th1: Th2, and Th0 and the Th1/Th2 cell ratios in human peripheral and endometrial T cells, Am. J. Reprod. Immunol. 42 (4) (1999) 240–245. M. Marzi, et al., Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy, Clin. Exp. Immunol. 106 (1) (1996) 127–133. B. Polgár, et al., Urinary progesterone-induced blocking factor concentration is related to pregnancy outcome, Biol. Reprod. 71 (5) (2004) 1699–1705. L. Li, J. Kang, W. Lei, Role of Toll-like receptor 4 in inflammation-induced preterm delivery, Mol. Hum. Reprod. 16 (4) (2010) 267–272. G. Dekker, B. Sibai, Primary, secondary, and tertiary prevention of pre-eclampsia, Lancet 357 (9251) (2001) 209–215. M.R. Shurin, et al., Th1/Th2 Balance in Cancer, Transplantation and Pregnancy. in Springer Seminars in Immunopathology, Springer, 1999. S.A. McCracken, et al., NF-(B-regulated suppression of T-bet in T cells represses Th1 immune responses in pregnancy, Eur. J. Immunol. 37 (5) (2007) 1386–1396. W.L. Chan, et al., Human IL-18 receptor and ST2L are stable and selective markers for the respective type 1 and type 2 circulating lymphocytes, J. Immunol. 167 (3) (2001) 1238–1244. D. Xu, et al., Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells, J. Exp. Med. 187 (5) (1998) 787–794. K. Nakanishi, et al., Interleukin-18 regulates both Th1 and Th2 responses, Annu. Rev. Immunol. 19 (1) (2001) 423–474. L. De Oliveira, et al., Proportion of invariant NKT cells in normal pregnant women at term: an evaluation in peripheral blood, placenta and umbilical cord blood, Am. J. Reprod. Immunol. 65 (1) (2011) 11–12. M.J. Kupferminc, et al. Tumor necrosis factor-α is elevated in plasma and amniotic fluid of patients with severe preeclampsia, Am. J. Obstet. Gynecol. 170 (5) (1994) 1752–1759. A. Ida, et al., IL-18 in pregnancy; the elevation of IL-18 in maternal peripheral blood during labour and complicated pregnancies, J. Reprod. Immunol. 47 (1) (2000) 65–74. Y. Daniel, et al., Plasma interleukin-12 is elevated in patients with preeclampsia, Am. J. Reprod. Immunol. 39 (6) (1998) 376–380. S. Saito, et al., The role of the immune system in preeclampsia, Mol. Aspects Med. 28 (2) (2007) 192–209. F. Azizieh, R. Raghupathy, M.a. Makhseed, Makhseed, maternal cytokine production patterns in women with pre-eclampsia, Am. J. Reprod. Immunol. 54 (1) (2005) 30–37. S.et al. Saito, Quantitative analysis of peripheral blood Th0, Th1, Th2 and the Th1: Th2 cell ratio during normal human pregnancy and preeclampsia, Clin. Exp. Immunol. 117 (3) (1999) 550. A.M. Germain, et al., Endothelial dysfunction a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events? Hypertension 49 (1) (2007) 90–95. G. Sacks, C. Redman, I. Sargent, Monocytes are primed to produce the Th1 type cytokine IL-12 in normal human pregnancy: an intracellular flow cytometric analysis of peripheral blood mononuclear cells, Clini. Exp. Immunol. 131 (3) (2003) 490–497. K.M. Adams, et al., Interleukin-18 in the plasma of women with preeclampsia, Am. J. Obstet. Gynecol. 188 (5) (2003) 1234–1237. M. Sakai, et al., The ratio of interleukin (IL)-18 to IL-12 secreted by peripheral blood mononuclear cells is increased in normal pregnant subjects and decreased in pre-eclamptic patients, J. Reprod. Immunol. 61 (2) (2004) 133–143. I.L. Sargent, A.M.C.W. Borzychowski Redman, NK cells and human pregnancy–an inflammatory view, Trends Immunol. 27 (9) (2006) 399–404. C. Prussin, B. Foster, TCR V alpha 24 and V beta 11 coexpression defines a human NK1 T cell analog containing a unique Th0 subpopulation, J. Immunol. 159 (12) (1997) 5862–5870. L.S. Metelitsa, et al., Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells, J. Immunol. 167 (6) (2001) 3114–3122.
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha
Review
Natural killer T cells in Preeclampsia: An updated review a,b,d
Vida Hashemi , Sanam Dolati ⁎ Mehdi Yousefic,d,
a,c,d
, Arezoo Hosseini
a,c,d
, Tohid Gharibi
a,c,d
MARK e
, Shahla Danaii ,
a
Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran Department of Basic Science, Faculty of Medicine, Maragheh University of Medical Sciences, Maragheh, Iran Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran d Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran e Gynecology Department, Eastern Azerbaijan ACECR ART Center, Eastern Azerbaijan Branch of ACECR, Tabriz, Iran b c
A R T I C L E I N F O
A B S T R A C T
Keywords: NKT cells Preeclampsia Pregnancy Cytokine
Preeclampsia (PE), as a pregnancy-specific syndrome, has become one of the main causes of maternal and fetal mortality worldwide and is known as a major risk factor for preterm birth. PE is typically characterized by hypertension, significant proteinuria, and an excessive maternal systemic inflammatory response. Recent evidences provide support for the notion that Natural killer T (NKT) cells (a small, but significant immunoregulatory T cell subset of human peripheral blood lymphocytes) play pivotal roles in pregnancy. NKT cells with unique transcriptional and cytokine profiles exist in different peripheral tissues acting as mediators between the innate and adaptive immune systems. NKT cells secrete Interleukin-4 (IL-4) and Interferon-γ (IFN-γ) which might regulate the balance between Type 1 T helper (Th1) and Type 2 T helper (Th2) responses. During pregnancy, maternal immunity is biased towards type II cytokine production to inhibit the function of type I cytokines that could be harmful for the developing fetus. This shift to type II cytokines does not occur in preeclamptic patients. In this review, we discuss the numbers, phenotype, changes, and the functional activity of Natural killer T (NKT) cells during normal pregnancy and preeclampsia.
1. Introduction As a specific disorder, preeclampsia (PE) occurs in the second half of pregnancy [1].The complications and their associated pathologies inherent in PE are known to be as the major causes of maternal and fetal morbidity as well as mortality across the globe [2–4]. For instance, PE is thought to be responsible for preterm birth, intrauterine growth restriction, and prenatal death in the fetus as well as in eclampsia and hemolysis and elevated liver enzymes and low platelet count(HELLP) syndrome in the mother [5]. Approximately 40% of premature births are reported to be delivered before 35 weeks of gestation [2]. Furthermore, preeclampsia is claimed to be the causative factor for nearly 12–25 percent of fetal growth restriction and 15–20 percent of preterm birth cases [6].Within the recent years, the rate of maternal morbidity and mortality associated with preeclampsia has shown a considerable decrease in developed countries [5]. However, there has been reported an increase in later-life death related to cardiovascular diseases, which is independent of other risk factors [2,4]. Moreover, preeclampsia is prevalent in women who experience their first pregnancy or carry twins [7]. High blood pressure
⁎
(≥ 140 mm Hg systolic or ≥ 90 mmHg diastolic on ≥ 2 occasions at least 6 h apart) [8], proteinuria [9], (at least 300 mg per 24 h) [5], and dysfunction of different organs [10] are hallmark characteristics of this clinical syndrome. There are also some risk factors associated with preeclampsia which include nulliparity, multifetal gestations, previous history of preeclampsia, obesity, diabetes mellitus, vascular and connective tissue disorders such as systemic lupus erythematosus and antiphospholipid antibodies syndrome, age > 35 years at first pregnancy, smoking, and African-American race [11]. Recently, it has been found that immune abnormalities make significant contributions to the pathogenesis of preeclampsia [12]. The findings have suggested that innate immunity play a more important role than adaptive immunity in the emergence of preeclampsia, especially increase of circulating monocytes, neutrophils and natural killer (NK) cells [13]. Also, it is of interest to note that there is an exacerbated maternal inflammatory response in patients with preeclampsia [14]. These responses may be attributed to the dominance of Th1 cells [15]. Natural killer T (NKT) cells are recognized as a distinct subset of
Corresponding author at: Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. E-mail addresses: Yousefi[email protected], mehdi_yusefi@yahoo.com (M. Yousefi).
http://dx.doi.org/10.1016/j.biopha.2017.08.077 Received 27 April 2017; Received in revised form 19 August 2017; Accepted 19 August 2017 0753-3322/ © 2017 Elsevier Masson SAS. All rights reserved.
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al.
lineage of iNKT cells known as NKT10 cells [40]. Type II variant NKT cells (VNKT) [28] are defined as CD1d-dependent T lymphocytes that do not express the invariant TCR-α chain and cannot recognize the lipid antigen α-GalCer [41]. VNKT cells are able to express a more diverse range of T-cell receptors (TCRs), and often play roles conflicting or cross-regulatory with iNKT cells [28]. VNKT cells are also more abundant in human than mouse [42]. Here, we focus on Type I NKT cells [43]. iNKT cells can be subdivided into NKT1, NKT2, NKT17, NKTFH, NKT10 regulatory and Foxp3+ iNKT cells [26,44]. The maturation of these cells in mouse consists of several distinct stages on the expression of CD24, CD44 and NK1.1 molecules. The most immature stage of iNKT cells is defined as stage 0 (CD24 high CD44lowNK1.1−) which is followed first by stage 1 (CD24lowCD44lowNK1.1−) and then by stage 2 (CD24lowCD44highNK1.1). Mature iNKT cells (Stage 3) are subdivided into at least three distinct populations, including NKT1 (CD4+/− NK1.1+), NKT2 (CD4+ NK1.1−), and NKT17 (CD4− NK1.1−) [45,46]. NKT1 and NKT2 mainly reside in non-lymphoid organs, while NKT17 cells are found in the peripheral lymph nodes (Fig. 1) [26]. NKT1,when activated, express high levels of T-bet and produce IFNγ [47]. These cells have also been demonstrated to express IL-15Rα (CD122) and loss of IL-15 also resulted in loss of NKT1 cells [48]. However, loss of T-bet or functional IL-15 has been found to enhance the number of NKT2 and NKT17 cells [47,49]. Recent findings have suggested that the transcription factor inhibitor of DNA binding 2(ID2) is highly upregulated in the NKT1 sublineage [50]. NKT2 cells, which are similar to Th2 cells, are characterized based on the cell surface expression of CD4 and interleukin-17 receptor B (IL17RB) [51]. Moreover, these cells are able to produce interleukin-4 (IL4) and interleukin-13 (IL-13). IL-17RB has been shown to be expressed also by NKT17 cells [49]. A new subset of CD4, NK1.1 NKT cells, has been identified which are characterized by their ability to produce very high amounts of IL-17 (NKT-17) early after being activated without the need for polarization [52–54]. NKT-17 cells express retinoic-acid-receptor-related orphan receptor (ROR) γt and Interleukin-23 receptor (IL-23R) [55]. Natural killer T follicular helper (NKTFH) cells trigger specific antibody responses and germinal center reactions (GCs). NKTFH cells containing CD4+,CD44high,programmed cell death protein 1(PD-1+), CX-C chemokine receptor type 5,(CXCR5)+, B-cell lymphoma 6 protein (Bcl6+) and the capacity for IL-21 secretion display high similarities to TFH cells. New findings highlight the significant role of NKTFH cells during antibody responses to protein [56,57], lipid, and carbohydrate antigens [58]. Recently, invariant NKT(iNKT) cells have been found to adopt the phenotype of TFH cells and to be localized within GCs. This finding is consistent with their ability to provide help for cognate B cells. The same procedure is required to differentiate iNKTFH and TFH cells [56] except for the fact that IL-21 is not needed for iNKTFH cell formation, even though it is crucial to their cognate functions [59]. NKT10 regulatory cells have a new surface phenotype and are able to produce a different cytokine pattern such as production of IL-10, a cytokine which mediates immune suppression. This capacity of NKT10 regulatory cells has served as a basis for suggesting the name “induced NKT10 cells”. In addition, FOXP3 is required for the proper functioning of regulatory T cells (Tregs) [60]. Moreover, the expression of this transcription factor can be induced in iNKT cells [61,62]. However, NKT10 cells do not induce FOXP3 [63]. NKT10 cells possess some properties of regulatory T cells including the increased expression of cytotoxic T-lymphocyte associated protein 4 (CTLA4), neuropilin1(Nrp1), and folate receptor 4 (FR4) [64]. Understanding the function of NKT10 subset may lead to obtaining deep insights into the anti-inflammatory role of iNKT cells in a variety of disease settings. It has been revealed that high expression levels of IL-10 mRNA are related to the
peripheral leukocytes [3]. Once activated, NKT cells secrete cytokines and boost the immune response which is triggered by a variety of interactions between NKT cells and other cell types including conventional CD4+ T and CD8+ T cells, dendritic cells (DCs), Natural killer (NK) cells, B cells, T regulatory (Treg) cells, macrophages and neutrophils [16]. These cells impact on large variety of immunological responses which include autoimmunity [17], antimicrobial host responses [18], resistance to tumors and transplantation immunity [19]. that are also increasingly activated in PE [3]. Some studies have provided supporting evidence for the possible significant role of NKT cells in pregnancy and preeclampsia. Consistent with this, it has been reported that treatment of pregnant mice with αGalactosylceramide (α-GalCer) leads to the occurrence of abortion which might be attributed to the release of Interferon gamma (IFN-γ) by NKT cells [20,21]. Also, there are some convincing data highlighting a strong link between NKT cells and priming Type 2 T helper (Th2) immune responses [22]. Furthermore, it has been demonstrated that both NK cells and proliferating cells, which are crucial to the progression and success of pregnancy, are regulated by NKT cells [23]. Based on these facts which imply the importance of NKT cells in the emergence of preeclampsia, the current review aims to investigate the roles that NKT cells play in the pathogenesis of this condition. 2. Natural killer T subsets NKT cells, which were first described in the late 1980s as innate-like lymphocytes [24] are known to be a new lymphocyte lineage [25]. These cells are characterized by the presence of Natural killer cells (NK cells) receptors with an invariant α-chain, NKT cells express αβTCR [26]. NKT cells are representative of a group of T lineage cells of thymic origin which have a variety of features. These features can be used to describe how NKT cells are different from ‘conventional T cells’ [26,27]. NKT cells recognize lipid antigens (mainly glycolipids) in the context of CD1d, a non-polymorphic major histocompatibility complex (MHC) class I-like molecule [27]. CD1d is expressed by hematopoietic cells [28] and on the surface of villous or extravillous trophoblasts [29] to interact with NKT cells in the deciduas [30]. The amion and the placenta are riched for sphingoglycolipids, many of which are gangliosides-containing sialic acid [31] that perhaps presented in the context of CD1d and recognized by NKT cells [32]. So it is vital to explain the roles of NKT cells-restricted CD1 that reside at the feto-maternal interface during pregnancy [33]. NKT cells are used to name some subsets of T lymphocytes, which are distinct in their phenotype, functional capacities and tissue distribution. There are two distinct types of NKT cell subpopulations [34] known as Type I and Type II lymphocytes [35]. NKT cells develop in the thymus, at least for the invariant NKT (iNKT) cells (Type I) cell lineage. There are numerous lines of convincing evidence highlighting that these cells undergo positive and negative selections [28]. Type I iNKT cells comprise a small, but significant immunoregulatory T-cell subset [29]. These cells express canonical TCRα chains which consist of certain gene segments, Vα14-Jα18 in mouse and Vα24-Jα18 in human. Furthermore, they preferentially pair with specific TCRβ chains including Vβ8, Vβ7, or Vβ2 in mouse and Vβ11 in human [24]. The majority of decidual NKT cells as well as other tissues such as bone marrow and liver and peripheral blood in human express Vβ11 [36]. iNKT cells are capable of recognizing a spectrum of bacteria-derived lipids. In addition, iNKT cells can also recognize endogenous lipids [37]. This property provides them with the ability to mature DCs and B cells in a CD40-dependent manner [38]. iNKT cells are able to quickly release both Th1-type and Th2-type cytokines (IFN-γ, TNF-α, IL-10 and IL-4) [39] in response to α-Galactosylceramide (α-GalCer). αGalCer is also thought to have the capacity for inducing a distinct 413
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al.
Fig. 1. NKT cell Subpopulations: NKT cells are representative of a group of T lineage cells of thymic origin which have a variety of features. They recognize lipid antigens (mainly glycolipids) in the context of CD1d, a non-polymorphic major histocompatibility complex (MHC) class I-like molecule, NKT cells are distinct in their phenotype, functional capacities and tissue distribution. There are two distinct types of NKT cell subpopulations known as iNKT cells (Type I) and VNKT cells (Type II). VNKT cell do not express the invariant TCR-α chain and cannot recognize the lipid antigen α-GalCer, also able to express a more diverse range of TCRs, and often play roles conflicting or cross-regulatory with iNKT cells. iNKT cells comprise a small, but significant, immunoregulatory T-cell subset, These cells are able to quickly release both Th1- type and Th2- type cytokines in response to α-Galactosylceramide (α-GalCer). As well as iNKT cells can be subdivided into at least 6 distinct from iNKT precursor cells in mouse. This categorization is performed based on the expression of CD24, CD44 and NK1.1 molecules. Each terminally differentiated lineage is defined by expression of a unique selection of cytokines and transcription factors. NKT1 cells express high levels of Tbet and release IFN γ and some IL-4 upon activation as well as express CD122, NK1.1. NKT2 cells continually express Gata3, CD4 and predominantly release IL-4 and IL-13 upon activation. NKT17 cells express ROR γt, IL-23R, CD4 and release IL-17 upon activation. NKTFH express the transcription factor Bcl6, CXCR5 and develop after activation although it also releases IL-21. NKT10 cells, although, these cells can be defined by IL-10 production as well as expression of NRP-1,FR4 and PD1. F0XP3 NKT cells express FOXP3, GITR, CTLA-4 and PLZF also release TGF-β.
than in peripheral blood (10 times) [29,68]. The iNKT cells present in the decidual tissue are involved in the maintenance of pregnancy in both humans and mice. NKT cells (CD3+/CD161 + ) might control the balance of Th1/Th2 at the maternal-fetal interface [68]. Also, the role of NKT cells in abortions is complicated [69]. NKT cells express not only T cell marker (CD3) but also NK cell markers [70] such as NK1.1 in mice (CD161 in human) [71]. Furthermore, CD161(is a C-type lectin receptor) which activates NK cell cytotoxicity [72]. In general, murine NKT cells carry an antigen has been recently characterized as CD49b, it is a 150 kD integrin α chain also known as α2 integrin(DX5) [3–5],also these cells express lectin-like type II transmembrane disulfide-bonded homodimer expressed on natural killer (NK) cells and some T-cell subsets(Ly-49) receptors, NKG2 (family Ctype lectin) receptors, and CD94 [24]. Human NKT cells often express surface molecules including CD56 [24,27], CD161 [27,35], CD94 and natural killer group 2D (NKG2D), NKG2A, CD16, and CD69 [71]. Although CD8+ NKT cells are found in human, they are rare in mouse. Recently, some reports have described phenotypic differences between CD4+ and CD4− iNKT cell subsets [73]. While the primary function of CD4− iNKT cells seems to be the secretion of Th1-type cytokines such as interferon gamma (IFN- γ) and tumor necrosis factorα (TNF-α). CD4+iNKT cells have been reported to be capable of producing both Th1-type and Th2-type cytokines. [29].
post-activated host iNKT cells. This observation may provide the possibility of early research on the NKT10 sublineage [65]. Several lines of evidence have indicated that, in certain settings, iNKT cells could be induced to express Foxp3 [61,62]. Foxp3+ iNKT cells indicate the phenotypic hallmarks of Treg cells including the expression of CD25, glucocorticoid-induced TNFR (GITR), and CTLA-4; while, they retain NKT cell-specific characteristics such as promyelocytic leukaemia zinc finger protein (PLZF) expression [62]. Both human and mouse-derived iNKT cells stimulated in vitro by transforming growth factor beta 1 (TGF-β) may be induced to express Foxp3. However, human-derived Foxp3+ iNKT cells, when generated in vitro in the presence of both TGF-β and rapamycin, could only suppress the proliferation of conventional T cells [61].
3. NKT cell numbers and phenotype during normal pregnancy and preeclampsia NKT producers of regulatory cytokines involved in controlling ovulation [66]. In mouse, NKT cell population comprises nearly 1% of peripheral lymphocytes. Moreover, the number of NKT cells in the peripheral blood mononuclear cells of human tends to be even less than mouse ranging from 0.01% to 1% [26]. As a minor population in the peripheral blood, peripheral NKT cells may have less significance during the reproductive process [67]. The other point is that NKT cells have larger numbers in the decidua 414
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al.
CD3+CD56+ cells can be divided into two subsets: CD3+CD56+CD16− and CD3+CD56+CD16+ [74]. Among these, CD3+CD56+CD16− subset might be harmful to fetal tolerance. In line with this, the increased numbers of CD3+CD56+CD16− NKT cell subset have been indicated to correlate with post-implantation pregnancy loss [75]. However, these two cell subsets display remarkable differences. Southcombe et al. compared the number and phenotype of iNKT cells in preeclamptic and normal pregnant women and found that these two groups have no discrepancy between the number of NKT cells per mL of blood and the percentage of iNKT cells. Also, there was no change observed in the proportion of iNKT cells expressing CD4 or CD8 markers as well as in the expression of the early activation marker CD69 by iNKT cells. Moreover, normal pregnant women indicated a slight decrease in the number of iNKT cells producing IFN-γ compared with preeclamptic women [76]. Another study reported that the increased number of NKT cells in blood may lead to recurrent pregnancy loss (RPL) [66]. It has been shown in the mouse that Vα14 NKT cell population is stimulated by a CD1d-restricted ligand and α-Galactosylceramide (α-GalCer) to produce type-I cytokines resulting in occult pregnancy loss and a homologous population of NKT cells (CD3+CD161+Vα24+), recognizing the same ligand, has been identified in humans [77]. Also, the ratio of peripheral blood NKT1/NKT2 cells seems to be higher in preeclamptic women than normal pregnant ones [69]. Previously, it has been indicated that NKT cell numbers are reduced in the decidua of women with recurrent miscarriages [78]. Borzychowski et al. reported significantly decreased NKT1⁄NKT2 cell ratios in normal pregnancy compared with pre-eclamptic women [79]. Boyson and et al. found the accumulation of IFN-γ-producing iNKT cells in the decidua of normal pregnant women, while their peripheral blood CD4+ iNKT cells exhibited a Th2 profile (IL-4, IL-5, IL-6, IL-10) [29]. Moreover, it has been reported that the expression of CD95 on the iNKT cells of healthy pregnant women is significantly higher than iNKT cells derived from preeclamptic patients [15]. In preeclamptic patients, the percentage of potential cytotoxic perforin expression by iNKT cells is significantly elevated compared with normal women. Furthermore, the number of iNKT cells co-expressing NKG2A and NKG2D receptors is significantly lower in preeclamptic patients than normal women [15].
Moreover, the activation of human antigen-presenting cells (APCs) by toll-like receptor (TLR) ligands modulates the lipid biosynthetic pathway. This process results in enhanced recognition of lipids by iNKT cells, which are certified by IFN- γ secretion and elevates the rate of CD1d-restricted iNKT cell activation [19]. In first trimester extravillous trophoblasts cells express CD1d and probably interact with maternal iNKT cells for normal placentation and implantation [15]. The pathophysiology of preeclampsia is recognized initial at pregnancy, where increased decidual iNKT activity can lead to poor trophoblasts invasion of the spiral arteries and placental insufficiency, even though later events comprise a systemic inflammatory response [15]. Invariant NKT cells in 3rd trimester peripheral blood of women with preeclampsia show a Th1 phenotype and therefore might take an active part in creating a systemic inflammatory dysfunction. Newly, Borzychowski et al. showed meaningfully reduced NKT1 > ⁄NKT2 cell ratios in normal pregnancy compared with nonpregnant and preeclamptic women [79]. On iNKT cells of preeclamptic patients, there is a changed balance of NK cell activating and inhibitory receptors. In preeclamptic women iNKT cells have a poorer chance to transduce inhibitory signals than those of healthy pregnant women. Peripheral Vα24 iNKT cells of preeclamptic women exhibited a Th1 dominant profile. The percentage of activated iNKT cells in preeclamptic women was expressively higher, and the same cells secreted more IFN-γ, contained more perforin, and exposed a decreased apoptotic potential compared to normal pregnancy [15]. In preeclampsia iNKT cells are activated, which may, be due to the altered expression of the NK cell inhibitory and activating receptor repertoire of the cells. Furthermore, because of their reduced apoptotic potential, these activated cytotoxic cells could be longer lived than those in normal pregnancy [86]. Therefore, iNKT cells at the materno-fetal interface may be activated by self-lipid antigens versus soluble factors from APCs upon TLR signaling, and play a role in inflammation-induced preterm birth. Also, TLR4 is responsible for LPS-induced preterm birth [87]. In normal pregnancy, Boyson et al. established the accumulation of IFN-γ producing iNKT cells in the decidua, while peripheral blood CD4+ iNKT cells displayed a Th2 profile [69,88]. 2 A successful pregnancy depends on stimulating the production of Th2-type cytokines and inhibiting the production of Th1-type proinflammatory cytokines [89]. Th1 responses in human pregnancy may be suppressed via down-regulating the expression of nuclear factor κB (NFκB) and T-box transcription factor(T-bet) [90]. The anti-inflammatory mediators produced by Th2 cells, including IL-4, IL-10 and TGFβ, appear to be needed for the maintenance of pregnancy due to their immunosuppressive effects. By contrast, proinflammatory mediators secreted by Th1 cells, such as TNFα, IFN-γ and monocyte chemoattractant protein-1(MCP-1), act to cause abortion or preeclampsia [71]. (Table 1). 4 NKT cells may play important roles in the success of implantation and fetal tolerance. It is commonly believed that the adequate function
4. NKT cell function in normal pregnancy and PE There are numerous reports in the literature highlighting the importance of NKT cells in human pregnancy. As mentioned before, NKT cells produce both Th1-type (IFN- γ) and Th2-type (IL-4) cytokines and control the function of T-helper cells (Th cells) at the materno-fetal interface [68]. Furthermore, the activities of NKT cells that result in cytotoxic effects are mediated by perforin/granzyme B and Fas ligand. It is interesting that functional molecules are used differentially by NKT cells under different circumstances [25]. TGF-β, TNF-α IFN- γ, IL-2, IL4, and IL-17 are pro- and anti-inflammatory cytokines which can be generated by activated NKT cells. It has been reported that mature IL-12 induced NKT cells can secrete type-1 cytokines [80]. NKT cells secrete IL-4 and IFN-γ cytokines which might be involved in regulating Th1/Th2 balance in the endometrial tissue [81]. At the feto-maternal interface [82], in pregnancy and in preeclampsia [83], this process is crucial to the immunological success of pregnancy. Th1 cells predominate the nonpregnant endometrium, especially during the proliferative phase; while Th2 cells predominate decidua in early pregnancy [84]. Th1 dominance seems to be associated with reproductive failures in preeclampsia; however, it has been reported that peripheral blood mononuclear cells show decreased IL-10 and increased IL-2 and IFN- γ production during spontaneous abortions [85]. Abortion occurs when NKT cells are activated by αGal-Cer [68].
Table 1 Profile of NKT cell-produced cytokines in preeclampsia and normal pregnancy. Preeclampsia
Normal pregnancy
TNF-ɑ IL-18 IL-12 MCP-1 IL-18R IL12P70 IFn- γ
IL-4 IL-10 TGF-β ST2L(IL1R)
There is a shift toward Th1-type cytokines in preeclampsia with increased proinflammatory cytokines, but toward Th2-type cytokines in normal pregnancy.
415
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al.
5. Changes in peripheral NKT cell populations in normal pregnancy and PE
of cytokine network is of particular importance for maintaining pregnancy. This finding is consistent with “immunothrophic hypothesis” which postulates that during the physiological pregnancy, the balance of Th1/Th2 activity strongly shifts toward Th2 activity. Therefore, Th1 activity is incompatible with a successful pregnancy [71]. In preeclampsia, the bias is toward type 1 immunity which is similar to nonpregnant women [79]. 6 There are two stable and universal surface markers for type-1 and type-2 subsets [91]. IL-18 receptor (IL-18R) is selectively expressed on type 1 lymphocyte lineages and stimulation expressed gene 2 a membrane-bound receptor (ST2L), a homologue of IL-1R, is selectively expressed on type 2 lymphocyte lineages in mouse and human[91,92]. Both ST2L and IL-18R are members of the TLR superfamily. In addition, IL-18 induces IFN-γ production from Th1 and NK cells [93]. These changes in the proportion of iNKT cells may be crucial for the maintenance of an adequate cytokine balance, which is necessary for a successful pregnancy [94]. The elevated serum levels of TNF-α [95], and IL-18 have been reported in preeclampsia (especially in HELLP syndrome) [96]. IL-18 is a cytokine which induces IFN-γ production and diverts Th1 predominant immunity in the presence of IL-12 [97]. The level of the Th2-type cytokine, IL-4, is the same between preeclamptic cases and normal pregnancy subjects in unstimulated peripheral blood mononuclear cell (PBMCs); however, the level of IL-4, stimulated by phytohemagglutiuin (PHA), is significantly lower in preeclamptic patients compared with normal pregnant women [98]. It seems that the balance of Th1-type to Th2-type cytokines shifts to Th1type immunity in preeclampsia [99]. These above findings suggest that Th1 type immunity is present in preeclampsia that the population of Th1 type cells increased, while Th2 type cells decreased in preeclampsia compared to those in healthy pregnancy(Fig. 2) [100] reported that there is a shift to the Type 1 bias of state in preeclampsia with increased proinflammatory circulating cytokines, such as IFN-γ, IL-12P70 and IL-18 [101].
The ability of iNKT cells to drive and modulate immune responses makes them ideal candidates for regulating immunity during pregnancy [67]. Of note, the population of uterine NKT cells is enriched after ovulation and during pregnancy[68]. Although the number of iNKT cells in blood remains constant throughout pregnancy, a slight decrease in CD69 expression on total iNKT cell population has been observed in the third trimester[76]. Peripheral blood leukocytes from normal pregnant woman are primed to produce higher levels of pro-inflammatory cytokines (IL-12, TNF-α, and IL-18) than those from nonpregnant women. However, IFNγ production is suppressed in normal pregnant women[102]. By contrast, it has been reported that although the levels of IL-12 and TNF-α production by peripheral blood leukocytes in preeclampsia are similar to those detected in normal pregnancy, IFN-γ levels shows significantly increased in preeclamptic individuals. Despite elevated cellular production of IL-18 in preeclampsia, this does not seem to be reflected in maternal plasma levels [103]. IL-18 alone can act as a Th2 cytokine. However, in the presence of IL-12, this cytokine functions synergistically to induce Th1 responses. It has also been found that a high ratio of IL-18 to IL-12 can result in shift toward Th2 responses during normal pregnancy, whereas a low ratio of IL-18 to IL-12 may account for Th1 bias and particularly increased levels of IFNγ production in preeclampsia [104].Thus, defining events seem to focus around IFN-γ production influenced by changes in IL-12 and IL-18 levels during pregnancy and preeclampsia. This question comes up as the source and stimulus of this cytokine production[105]. It has been demonstrated that treatment of pregnant mice with α-GalCer can lead to iNKT-mediated abortion. Several other observations have highlighted the fact that iNKT cells may play key roles in IFN-γ release during pregnancy and preeclampsia [20]. Furthermore, there is evidence indicating that iNKT cells are involved in priming Th2 immune responses [106]. iNKT cells have also been indicated to account for the activation and proliferation of NK cells which are known to be critical for the progression and success of Fig. 2. NKT cells in Pregnancy: Natural killer T (NKT (cells (a small, but significant immunoregulatory T cell subset of human peripheral blood lymphocytes) play pivotal roles in pregnancy. NKT cells with unique transcriptional and cytokine profiles exist in different peripheral tissues acting as mediators between the innate and adaptive immune systems. These cells secrete IL-4 and IFN-γ which might regulate the balance between Type Th1/Th2 responses. During Normal pregnancy, maternal immunity is biased towards type II cytokine (IL-4, TGF-β, IL-10) production to inhibit the function of type I cytokines (IL-12, IFN-γ, TNF-α, IL-18) that could be harmful for the developing fetus. This shift to type I cytokines with increased proinflammatory circulating cytokines occur in preeclamptic patients.
416
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al.
Immunol. 2 (8) (2002) 557–568. [22] N. Singh, et al., Cutting edge: activation of NK T cells by CD1d and α-galactosylceramide directs conventional T cells to the acquisition of a Th2 phenotype, J. Immunol. 163 (5) (1999) 2373–2377. [23] G. Eberl, H.R. MacDonald, Selective induction of NK cell proliferation and cytotoxicity by activated NKT cells, Eur. J. Immunol. 30 (4) (2000) 985–992. [24] J.B. Altman, et al., Antitumor responses of invariant natural killer t cells, J. Immunol. Res. (2015) 2015. [25] M. Taniguchi, T. Nakayama, Recognition and function of V (14 NKT cells, Semin. Immunol. (2000) (Elsevier). [26] A.M. Birkholz, M. Kronenberg, Antigen specificity of invariant natural killer Tcells, Biomed. J. 38 (6) (2015) 470–483. [27] V. Kumar, NKT-cell subsets: promoters and protectors in inflammatory liver disease, J. Hepatol. 59 (3) (2013) 618–620. [28] L. Van Kaer, V.V. Parekh, L. Wu, Invariant natural killer T cells: bridging innate and adaptive immunity, Cell Tissue Res. 343 (1) (2011) 43–55. [29] J.E. Boyson, et al., CD1d and invariant NKT cells at the human maternal?fetal interface, Proceedings of the National Academy of Sciences 99 (21) (2002) 13741–13746. [30] S. Shimada, et al., No difference in natural killer or natural killer T-cell population, but aberrant T-helper cell population in the endometrium of women with repeated miscarriage, Hum. Reprod. 19 (4) (2004) 1018–1024. [31] R. Rueda, K. Tabsh, S. Ladisch, Detection of complex gangliosides in human amniotic fluid, FEBS Lett. 328 (1–2) (1993) 13–16. [32] D.Y. Wu, et al., Cross-presentation of disialoganglioside GD3 to natural killer T cells, J. Exp. Med. 198 (1) (2003) 173–181. [33] T. Kawano, et al., CD1d-restricted and TCR-mediated activation of V(14 NKT cells by glycosylceramides, Science 278 (5343) (1997) 1626–1629. [34] E. Peralbo, C. Alonso, R. Solana, Invariant NKT and NKT-like lymphocytes: two different T cell subsets that are differentially affected by ageing, Exp. Gerontol. 42 (8) (2007) 703–708. [35] W.L. Chan, et al., NKT cell subsets in infection and inflammation, Immunol. Lett. 85 (2) (2003) 159–163. [36] C. Couedel, et al., Diverse CD1d-restricted reactivity patterns of human T cells bearing invariant AV24BV11 TCR, Eur. J. Immunol. 28 (12) (1998) 4391–4397. [37] A.P. Lawton, et al., The mouse CD1d cytoplasmic tail mediates CD1d trafficking and antigen presentation by adaptor protein 3-dependent and-independent mechanisms, J. Immunol. 174 (6) (2005) 3179–3186. [38] I.F. Hermans, et al., NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells, J. Immunol. 171 (10) (2003) 5140–5147. [39] G. Galli, et al., CD1d-restricted help to B cells by human invariant natural killer T lymphocytes, J. Exp. Med. 197 (8) (2003) 1051–1057. [40] P.J. Brennan, M. Brigl, M.B. Brenner, Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions, Nat. Rev. Immunol. 13 (2) (2013) 101–117. [41] S. Stankovic, et al., Distinct roles in NKT cell maturation and function for the different transcription factors in the classical NF-κB pathway, Immunol. Cell Biol. 89 (2) (2011) 294–303. [42] P. Arrenberg, I. Maricic, V. Kumar, Sulfatide-mediated activation of type II natural killer T cells prevents hepatic ischemic reperfusion injury in mice, Gastroenterology 140 (2) (2011) 646–655. [43] D.I. Godfrey, et al., NKT cells: what's in a name? Nat. Rev. Immunol. 4 (3) (2004) 231–237. [44] H.M. Buechel, M.H. Stradner, L.M. D’Cruz, Stages versus subsets: invariant natural killer T cell lineage differentiation, Cytokine 72 (2) (2015) 204–209. [45] R. Das, D.B. Sant’Angelo, K.E. Nichols, Transcriptional control of invariant NKT cell development, Immunol. Rev. 238 (1) (2010) 195–215. [46] E.Y. Kim, et al., The transcriptional programs of iNKT cells, Semin. Immunol. 27 (1) (2015) 26–32 (Elsevier). [47] Y.J. Lee, et al., Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells, Nat. Immunol. 14 (11) (2013) 1146–1154. [48] J.L. Matsuda, et al., Homeostasis of V(14i NKT cells, Nat. Immunol. 3 (10) (2002) 966–974. [49] H.et al. Watarai, Development and function of invariant natural killer t cells producing TH 2-and TH 17-Cytokines, PLoS Biol. 10 (2) (2012) e1001255. [50] L.M. D’, et al., E and Id proteins influence invariant NKT cell sublineage differentiation and proliferation, J. Immunol. 192 (5) (2014) 2227–2236. [51] A. Terashima, et al., A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity, J. Exp. Med. 205 (12) (2008) 2727–2733. [52] J.M. Coquet, et al., Diverse cytokine production by NKT cell subsets and identification of an IL-17?producing CD4- NK1. 1- NKT cell population, Proceedings of the National Academy of Sciences 105 (32) (2008) 11287–11292. [53] M.-L. Michel, et al., Identification of an IL-17?producing NK1. 1neg iNKT cell population involved in airway neutrophilia, J. Exp. Med. 204 (5) (2007) 995–1001. [54] R.R. Caspi, et al., NKT cells constitutively express IL-23 receptor and RORγt, and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion, FASEB J. 22 (Suppl. 1) (2008) (1069. 5-1069.5). [55] S. Stankovic, Distinct roles in NKT cell maturation and function for the different transcription factors in the classical NF-[kappa] B pathway, Immunol. Cell Biol. 89 (2) (2011) 294. [56] P.-P. Chang, et al., Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses, Nat. Immunol. 13 (1) (2012) 35–43.
pregnancy [107]. 6. Conclusion In the current article, we made effort to provide an overview of the roles played by NKT cells in preeclampsia. Numerous reports investigating the biological roles of NKT cells have highlighted the fact that these cells hold major roles in innate immunity. Different studies have shown that the number of these cells in decidua is higher than peripheral blood. In preeclampsia, the ratio of Th1-type to Th2-type cytokines shifts toward Th1-type immunity. A large body of evidence provides support for the notion that NKT cell numbers are significantly reduced in normal pregnancy compared with preeclampsia. However, no remarkable discrepancy has been observed in the iNKT cell number or phenotype between normal pregnancy and preeclampsia, even though normal pregnant women show a slight decrease in iNKT cell-secreted IFN-γ compared with preeclamptic patients. Overall, current findings lead to the postulation that when NKT subsets are preferentially induced, they are likely to contribute to preeclampsia. These data also highlight the role of NKT cells in regulating the Th1/Th2 balance as one of the essential functions of these cells in vivo. Both in decidua and peripheral blood, NKT cells are capable of modulating immune response through production of cytokines associated with Th1 (IFN- γ) and Th2 (IL-4, IL-10) cells. There is an imbalance between Th1 and Th2 responses in preeclamptic individuals and these patients show a predominant Th1-type immunity. References [1] S.J. Germain, et al., Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles, J. Immunol. 178 (9) (2007) 5949–5956. [2] A. Perez-Sepulveda, et al., Innate immune system and preeclampsia, Immune Interact. During Reprod. Cycle 5 (244) (2015) 130. [3] H. Ahn, et al., Immunologic characteristics of preeclampsia, a comprehensive review, Am. J. Reprod. Immunol. 65 (4) (2011) 377–394. [4] F.J. Valenzuela, et al., Pathogenesis of preeclampsia: the genetic component, J. Pregnancy 2012 (2011). [5] N. Hariharan, A. Shoemaker, S. Wagner, Pathophysiology of hypertension in preeclampsia, Microvasc. Res. 109 (2016) 34. [6] A. Jeyabalan, Epidemiology of preeclampsia: impact of obesity, Nutr. Rev. 71 (suppl. 1) (2013) S18–S25. [7] N. Al-Jameil, et al., A brief overview of preeclampsia, J. Clin. Med. Res. 6 (1) (2013) 1–7. [8] A. Molvarec, et al., Increased prevalence of peripheral blood granulysin-producing cytotoxic T lymphocytes in preeclampsia, J. Reprod. Immunol. 91 (1) (2011) 56–63. [9] I. Sargent, A. Borzychowski, C. Redman, NK cells and pre-eclampsia, J. Reprod. Immunol. 76 (1) (2007) 40–44. [10] S.I. Gilani, Preeclampsia and extracellular vesicles, Curr. Hypertens. Rep. 18 (9) (2016) 68. [11] E. Eiland, C.M. Nzerue Faulkner, Preeclampsia, J. Pregnancy 2012 (2012). [12] F. Liu, et al., Role of agonistic autoantibodies against type-1 angiotensin II receptor in the pathogenesis of retinopathy in preeclampsia, Sci. Rep. (2016) 6. [13] C.E. Leik, S.W. Walsh, Neutrophils infiltrate resistance-sized vessels of subcutaneous fat in women with preeclampsia, Hypertension 44 (1) (2004) 72–77. [14] J. Bueno-Sánchez, et al., Cytokine production by non-stimulated peripheral blood NK cells and lymphocytes in early-onset severe pre-eclampsia without HELLP, J. Reprod. Immunol. 97 (2) (2013) 223–231. [15] E. Miko, et al., The role of invariant NKT cells in Pre‐Eclampsia, Am. J. Reprod. Immunol. 60 (2) (2008) 118–126. [16] J.L. Matsuda, et al., CD1d-restricted iNKT cells: the ‘Swiss-Army knife’of the immune system, Curr. Opin. Immunol. 20 (3) (2008) 358–368. [17] A. Teige, et al., CD1d-dependent NKT cells play a protective role in acute and chronic arthritis models by ameliorating antigen-specific Th1 responses, J. Immunol. 185 (1) (2010) 345–356. [18] M. Emoto, et al., α-galactosylceramide promotes killing of Listeria monocytogenes within the macrophage phagosome through invariant NKT-cell activation, Infect. Immun. 78 (6) (2010) 2667–2676. [19] L.-P. Li, et al., Depletion of invariant NKT cells reduces inflammation-induced preterm delivery in mice, J. Immunol. 188 (9) (2012) 4681–4689. [20] J.E. Boyson, et al., Gestation stage-dependent mechanisms of invariant natural killer T cell-mediated pregnancy loss, Proc. Natl. Acad. Sci. U. S. A. 103 (12) (2006) 4580–4585. [21] M. Kronenberg, L. Gapin, The unconventional lifestyle of NKT cells, Nat. Rev.
417
Biomedicine & Pharmacotherapy 95 (2017) 412–418
V. Hashemi et al. [57] I.L. King, et al., Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner, Nat. Immunol. 13 (1) (2012) 44–50. [58] P. Rampuria, M.L. Lang, CD1d-dependent expansion of NKT follicular helper cells in vivo and in vitro is a product of cellular proliferation and differentiation, Int. Immunol. (2015) dxv007. [59] P. Dellabona, S. Abrignani, G. Casorati, iNKT-cell help to B cells: a cooperative job between innate and adaptive immune responses, Eur. J. Immunol. 44 (8) (2014) 2230–2237. [60] S. Sakaguchi, Regulatory T cells: history and perspective, Regul. T cells: Methods Protoc. (2011) 3–17. [61] L. Moreira-Teixeira, et al., Rapamycin combined with TGF-(converts human invariant NKT Cells into suppressive Foxp3+ regulatory cells, J. Immunol. 188 (2) (2012) 624–631. [62] M. Monteiro, et al., Identification of regulatory Foxp3+ invariant NKT cells induced by TGF-β, J. Immunol. 185 (4) (2010) 2157–2163. [63] D. Sag, et al., IL-10?producing NKT10 cells are a distinct regulatory invariant NKT cell subset, J. Clin. Invest. 124 (9) (2014) 3725–3740. [64] L. Fox, S. Hegde, J.E. Gumperz, Natural killer T cells: innate lymphocytes positioned as a bridge between acute and chronic inflammation? Microbes Infect. 12 (14) (2010) 1125–1133. [65] K. Oh, et al., Direct regulatory role of NKT cells in allogeneic graft survival is dependent on the quantitative strength of antigenicity, J. Immunol. 174 (4) (2005) 2030–2036. [66] J. Křížan, et al., Altered distribution of NK and NKT cells in follicular fluid is associated with IVF outcome, J. Reprod. Immunol. 82 (1) (2009) 84–88. [67] S. Shimada, et al., No difference in natural-killer-T cell population, but Th2/Tc2 predominance in peripheral blood of recurrent aborters, Am. J. Reprod. Immunol. 50 (4) (2003) 334–339. [68] H. Tsuda, et al., Characterization of NKT cells in human peripheral blood and decidual lymphocytes, Am. J. Reprod. Immunol. 45 (5) (2001) 295–302. [69] K. Ito, et al., Involvement of decidual Vα14 NKT cells in abortion, Proc. Natl. Acad. Sci. 97 (2) (2000) 740–744. [70] E.I. Ntrivalas, et al., Expression of killer immunoglobulin-like receptors on peripheral blood NK cell subsets of women with recurrent spontaneous abortions or implantation failures, Am. J. Reprod. Immunol. 53 (5) (2005) 215–221. [71] J. Zhou, et al., High circulating CD3+ CD56+ CD16+ natural killer-like T cell levels predict a better IVF treatment outcome, J. Reprod. Immunol. 97 (2) (2013) 197–203. [72] J.C. Ryan, et al., NKR-P1A is a target-specific receptor that activates natural killer cell cytotoxicity, J. Exp. Med. 181 (5) (1995) 1911–1915. [73] P.T. Lee, et al., Distinct functional lineages of human V(24 natural killer T cells, J. Exp. Med. 195 (5) (2002) 637–641. [74] M.J. Van Den Heuvel, et al., Decline in number of elevated blood CD3+ CD56+ NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy, Am. J. Reprod. Immunol. 58 (5) (2007) 447–459. [75] G. Hodge, et al., Increased natural killer T-like cells are a major source of proinflammatory cytokines and granzymes in lung transplant recipients, Respirology 17 (1) (2012) 155–163. [76] J. Southcombe, C. Redman, I. Sargent, Peripheral blood invariant natural killer T cells throughout pregnancy and in preeclamptic women, J. Reprod. Immunol. 87 (1) (2010) 52–59. [77] R.M. Gorczynski, et al., The same immunoregulatory molecules contribute to successful pregnancy and transplantation, Am. J. Reprod. Immunol. 48 (1) (2002) 18–26. [78] T. Yamamoto, et al., Proportion of CD56+ 3+ T cells in decidual and peripheral lymphocytes of normal pregnancy and spontaneous abortion with and without history of recurrent abortion, Am. J. Reprod. Immunol. 42 (6) (1999) 355–360. [79] A.M. Borzychowski, et al., Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells, Eur. J. Immunol. 35 (10) (2005) 3054–3063. [80] M.J. Loza, L.S. Metelitsa, B. Perussia, NKT and T cells: coordinate regulation of NK-like phenotype and cytokine production, Eur. J. Immunol. 32 (12) (2002) 3453–3462. [81] H. Chen, W.E. Paul, Cultured NK1. 1+ CD4+ T cells produce large amounts of IL4 and IFN-gamma upon activation by anti-CD3 or CD1, J. Immunol. 159 (5) (1997) 2240–2249. [82] R. Geiben-Lynn, et al., Non-classical natural killer t cells modulate plasmid DNA
[83] [84]
[85]
[86] [87] [88] [89] [90] [91]
[92] [93] [94]
[95]
[96]
[97] [98] [99]
[100]
[101]
[102]
[103] [104]
[105] [106]
[107]
418
vaccine antigen expression and vaccine-elicited immune responses by MCP-1 secretion after interaction with a (2-Microglobulin-independent CD1d, J. Biol. Chem. 284 (49) (2009) 33800–33806. S. Hori, T. Nomura, S. Sakaguchi, Control of regulatory T cell development by the transcription factor Foxp3, Science 299 (5609) (2003) 1057–1061. S. Saito, et al., Distribution of Th1: Th2, and Th0 and the Th1/Th2 cell ratios in human peripheral and endometrial T cells, Am. J. Reprod. Immunol. 42 (4) (1999) 240–245. M. Marzi, et al., Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy, Clin. Exp. Immunol. 106 (1) (1996) 127–133. B. Polgár, et al., Urinary progesterone-induced blocking factor concentration is related to pregnancy outcome, Biol. Reprod. 71 (5) (2004) 1699–1705. L. Li, J. Kang, W. Lei, Role of Toll-like receptor 4 in inflammation-induced preterm delivery, Mol. Hum. Reprod. 16 (4) (2010) 267–272. G. Dekker, B. Sibai, Primary, secondary, and tertiary prevention of pre-eclampsia, Lancet 357 (9251) (2001) 209–215. M.R. Shurin, et al., Th1/Th2 Balance in Cancer, Transplantation and Pregnancy. in Springer Seminars in Immunopathology, Springer, 1999. S.A. McCracken, et al., NF-(B-regulated suppression of T-bet in T cells represses Th1 immune responses in pregnancy, Eur. J. Immunol. 37 (5) (2007) 1386–1396. W.L. Chan, et al., Human IL-18 receptor and ST2L are stable and selective markers for the respective type 1 and type 2 circulating lymphocytes, J. Immunol. 167 (3) (2001) 1238–1244. D. Xu, et al., Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells, J. Exp. Med. 187 (5) (1998) 787–794. K. Nakanishi, et al., Interleukin-18 regulates both Th1 and Th2 responses, Annu. Rev. Immunol. 19 (1) (2001) 423–474. L. De Oliveira, et al., Proportion of invariant NKT cells in normal pregnant women at term: an evaluation in peripheral blood, placenta and umbilical cord blood, Am. J. Reprod. Immunol. 65 (1) (2011) 11–12. M.J. Kupferminc, et al. Tumor necrosis factor-α is elevated in plasma and amniotic fluid of patients with severe preeclampsia, Am. J. Obstet. Gynecol. 170 (5) (1994) 1752–1759. A. Ida, et al., IL-18 in pregnancy; the elevation of IL-18 in maternal peripheral blood during labour and complicated pregnancies, J. Reprod. Immunol. 47 (1) (2000) 65–74. Y. Daniel, et al., Plasma interleukin-12 is elevated in patients with preeclampsia, Am. J. Reprod. Immunol. 39 (6) (1998) 376–380. S. Saito, et al., The role of the immune system in preeclampsia, Mol. Aspects Med. 28 (2) (2007) 192–209. F. Azizieh, R. Raghupathy, M.a. Makhseed, Makhseed, maternal cytokine production patterns in women with pre-eclampsia, Am. J. Reprod. Immunol. 54 (1) (2005) 30–37. S.et al. Saito, Quantitative analysis of peripheral blood Th0, Th1, Th2 and the Th1: Th2 cell ratio during normal human pregnancy and preeclampsia, Clin. Exp. Immunol. 117 (3) (1999) 550. A.M. Germain, et al., Endothelial dysfunction a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events? Hypertension 49 (1) (2007) 90–95. G. Sacks, C. Redman, I. Sargent, Monocytes are primed to produce the Th1 type cytokine IL-12 in normal human pregnancy: an intracellular flow cytometric analysis of peripheral blood mononuclear cells, Clini. Exp. Immunol. 131 (3) (2003) 490–497. K.M. Adams, et al., Interleukin-18 in the plasma of women with preeclampsia, Am. J. Obstet. Gynecol. 188 (5) (2003) 1234–1237. M. Sakai, et al., The ratio of interleukin (IL)-18 to IL-12 secreted by peripheral blood mononuclear cells is increased in normal pregnant subjects and decreased in pre-eclamptic patients, J. Reprod. Immunol. 61 (2) (2004) 133–143. I.L. Sargent, A.M.C.W. Borzychowski Redman, NK cells and human pregnancy–an inflammatory view, Trends Immunol. 27 (9) (2006) 399–404. C. Prussin, B. Foster, TCR V alpha 24 and V beta 11 coexpression defines a human NK1 T cell analog containing a unique Th0 subpopulation, J. Immunol. 159 (12) (1997) 5862–5870. L.S. Metelitsa, et al., Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells, J. Immunol. 167 (6) (2001) 3114–3122.