Immunologic challenges of human reproduction: an evolving story

VIEWS AND REVIEWS 1 2 3 4 5 6 7 8 9 10 a b Q5 Kassie J. Hyde, M.D. and Danny J. Schust, M.D. 11 b Department of Obstetrics, Gynecology and Women's Hea...

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VIEWS AND REVIEWS 1 2 3 4 5 6 7 8 9 10 a b Q5 Kassie J. Hyde, M.D. and Danny J. Schust, M.D. 11 b Department of Obstetrics, Gynecology and Women's Health; a University of Missouri School of Medicine, Columbia, 12 Missouri 13 14 15 16 Characterization of the implanting human fetus as an allograft prompted a ﬁeld of research in reproductive immunology that continues 17 to fascinate and perplex scientists. Paternal- or partner-derived alloantigens are present in the maternal host at multiple times during 18 the reproductive process. They begin with exposure to semen, continue through implantation and placentation, and may persist for 19 decades in the form of fetal microchimerism. Changes in maternal immune responses that allow allogenic fertilization and survival of semiallogenic concepti to delivery must be balanced with a continued need to respond appropriately to pathogenic invaders, com20 mensals, cell or tissue damage, and any tendency toward malignant transformation. This complex and sophisticated balancing act is 21 essential for survival of mother, fetus, and the species itself. We will discuss concepts of alloimmune recognition, tolerance, and igno22 rance as they pertain to mammalian reproduction with a focus on human reproduction, maternal immune modulation, and the very 23 earliest events in the reproductive process, fertilization and implantation. (Fertil SterilÒ 2016;-:-–-. Ó2016 by American Society 24 for Reproductive Medicine.) 25 Key Words: Reproductive immunology, implantation, placenta, fertilization, allograft 26 Discuss: You can discuss this article with its authors and with other ASRM members at 27 28 29 30 31 32 regnancy poses perhaps one of derived (fetal) antigens on the leadnanoparticles and microparticles, 33 the most unique and chaling edge syncytiotrophoblast may and exosomes into the maternal cir34 lenging tasks for the immune be accessible during initial embryo culation, [b] soluble forms of the 35 system. The female reproductive tract implantation; [3] at the surface of nonclassic major histocompatibility 36 must balance protection from pathothe syncytiotrophoblast layer of the complex (MHC) class I molecule 37 genic infections and inﬂammatory villous placenta, which is bathed in HLA-G are secreted into the maternal 38 insults with acceptance of speciﬁc maternal blood; [4] within the circulation, and [c] fetal cells trafﬁc 39 foreign antigens to support reprodecidua of the more mature, after iminto the maternal circulatory system 40 ductive function. There are several plantation, placenta when invading where they can remain in tissues 41 sites and times at which the maternal extravillous trophoblast cells interact for decades (fetal microchimerism). 42 immune system may be challenged with decidual immune cells as they In the absence of an appropriate 43 with fetal/paternal/partner alloantitraverse this tissue to reach the inner response in female immunoregula44 gens during the course of successful third of the myometrium (in tory and immunosuppressive activ45 reproduction. These include: [1] humans), remodel, and replace the ities to these non-self antigens, the 46 within the female genital tract when supporting cells of the maternal spisurvival of the human species would 47 partner/paternal antigens are introral arteries; and [5] more systemibe at risk. Given the enormity of this 48 duced by semen and sperm to allow cally within the mother when [a] responsibility, it comes as no surprise 49 fertilization; [2] within the early syncytiotrophoblast turnover at the that the mechanisms involved are 50 maternal decidua when paternally villous interface sheds microvesicles, complex and redundant (1). Like 51 other mucosal surfaces, the epithelial 52 components and subepithelial im53 Received May 6, 2016; revised and accepted July 13, 2016. mune cells of the female genital tract K.J.H. has nothing to disclose. D.J.S. has nothing to disclose. 54 serve as the initital barrier to and Reprint requests: Danny J. Schust, M.D., Department of Obstetrics, Gynecology and Women's Health, 55 University of Missouri School of Medicine, 500 North Keene Street, Suite 203, Columbia, Missurveyor of all incoming antigens. 56 souri 65201 (E-mail: [email protected]). Immune responses at these sites 57 Fertility and Sterility® Vol. -, No. -, - 2016 0015-0282/$36.00 must reliably target pathogen58 Copyright ©2016 American Society for Reproductive Medicine, Published by Elsevier Inc. derived antigens for destruction, http://dx.doi.org/10.1016/j.fertnstert.2016.07.1073 59

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yet, simultaneously tolerating antigens of commensal organisms, semen, and the fetal allograft (2). Endocrine and immunologic mechanisms work to alter the cellular, cytokine, and chemokine environments at mucosal interfaces within the female reproductive tract to promote tolerance of speciﬁc non-self antigens. Speciﬁc glycosylation patterns expressed on non-self cells, such as placental trophoblast cells or human gametes, may also play a speciﬁc role in immune regulation (1). These and several other mechanisms will be discussed in this article. At present, researchers in the ﬁeld of reproductive immunology have concentrated the lion's share of their energies on immunologic changes surrounding acceptance of the fetal allograft. This focus was largely driven by the classic articles of Sir Peter Medawar and colleagues (3) in the early 1950s that proposed the immunologic conundrum of the fetal allograft in humans. For several years, studies in this area focused on immunologic ignorance as central to this process. It was hypothesized that the mother simply did not recognize her fetus as foreign and therefore did not mount an alloimmune response. Reports on the presence of circulating antipaternal antibodies in maternal sera suggested that mammalian females, including humans, do indeed recognize paternally derived antigens on their allogeneic concepti, at least during later stages of pregnancy when the implanting fetus has invaded into the maternal decidua (4–8). The overarching hypothesis for most of the pregnancy therefore changed from ignorance to tolerance of the fetus. The latter requires substantial maternal immune deviations during pregnancy. These alterations are not simply reductions in immune responsiveness, but are much more nuanced. They may also differ before and after implantation. In fact, although pregnancy has generally been considered a time of at least local immune suppression, several lines of evidence indicate that the local environment at the implantation site in humans is proinﬂammatory (9). These observations have been used to explain the beneﬁcial effects of endometrial injury on implantation and pregnancy success in patients undergoing assisted reproduction (9, 10). Likewise, human pregnancy, particularly in the third trimester, has been characterized as a period of maternal systemic inﬂammation (11). This state appears to be to be magniﬁed in women experiencing preeclampsia (11, 12) and may represent one aspect of preparation for labor in all women (13). The best characterization of the immune state in successful pregnancy, however, is neither inﬂammatory nor immunosuppressed but rather one of tightly controlled and complex immune modulation. The characteristics of this modulation likely differ during the course of pregnancy. Some may be quite pronounced locally but less so systemically. Some of these changes appear to proceed the time of implantation, with its resultant exposure of fetal antigens to the maternal immune system. Some can even be detected even before conception. Finally, characterization of pregnancy as a state of solely immune tolerance or immune ignorance of paternal alloantigen is almost certainly an oversimpliﬁcation. Both are likely involved, in time- and location-speciﬁc manners.

IMMUNOLOGIC INTERACTIONS IN THE FEMALE REPRODUCTIVE TRACT: A FOCUS ON TOLERANCE The immune system can be divided into two discrete compartments: peripheral and mucosal. Most of the general immunologic principles have been best investigated and described for the peripheral immune system. During the past few decades, our understanding of the mucosal immune compartment has grown rapidly. Charged with the responsibility for defense against blood-borne pathogens, the peripheral immune system primarily consists of the spleen, lymph nodes, and peripheral blood. In contrast, as part of the innate defense system, the mucosal immune system serves to provide protection against pathogens that gain exposure to the body through the mucosal surfaces of the respiratory and gastrointestinal tracts, lacrimal ducts, mammary ducts, and genitourinary tract (14). This combined mucosal surface area of several hundred square meters protects from antigens in ingested food, inhaled particles, and resident microorganisms using a combination of T cells, B cells (including IgA-secreting plasma cells), natural killer (NK) cells, macrophages, and dendritic cells. Humoral factors, including lysozyme, lactoferrin, peroxidase, mucins, defensins, and digestive enzymes, also play key roles in defending the mucosal compartment (14, 15). Although the female reproductive tract is a component of the mucosal immune system, immunologic interactions at the surface of the female genital tract can differ from those manifested in the peripheral compartment and at other mucosal immune sites (16). Particularly notable in these cycling tissues is the strong hormonal control that dictates the transport of immunoglobulins, levels of cytokines, quality of antigen presentation, and distribution of certain immune cell populations. Hormonal contributions to immune regulation are particularly evident during pregnancy when systemic and local levels of pregnancy-related steroid and protein hormones are dramatically altered by the presence of the fetalplacental unit. Still, while supporting physiologic events, such as fertilization, implantation, pregnancy, and parturition, the mucosal immune system of the female genital tract must continue to protect against infectious pathogens and tolerate commensals (14). The female immune system undergoes constant transformation and adaptation beginning with each menstrual cycle and continuing through gestation in the event of fertilization. For example, compared with the mucosa of the gut or lung, the mucosal surface of the female reproductive tract requires more extreme MHC-related tolerance mechanisms that enable it to endure prolonged exposure to HLA-mismatched developing embryos (2). Data from animal and human studies indicate that immune cells at the maternal-to-fetal interface are selected and maintained in ways that differ from immune cells in the periphery as well as in other mucosal locations (17, 18). Furthermore, investigations have shown the existence of particular cellular homing mechanisms to recruit these speciﬁc cell populations to the reproductive tract (19, 20). Changes in immune cell populations and secretory proﬁles in the decidua that promote allograft

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Fertility and Sterility® acceptance are not the only sites where one can document immune changes during the before and peri-implantation stages of pregnancy. The oviducts and uterus provide cytokines and soluble factors to promote blastocyst development, modulate embryo metabolic function and gene expression, and increase implantation success (21, 22). Among the many contributors to this localized immune regulation, some of the most important mechanisms include the presence of unique immune cell populations, alterations in T-cell proﬁles, and the immune effects of gestationassociated hormones.

Immune Cells Populating the Female Reproductive Tract The female genital tract contains at least ﬁve notable and unusual immune cell types that deserve speciﬁc mention: decidual granular lymphocytes, NKT cells, T-cell receptor (TCR)gdþ cells, decidual macrophages, and innate lymphoid cells (Fig. 1). During the menstrual cycle, resident cell populations of the human endometrium undergo dramatic changes. One remarkable immune cell type, called decidual granular lymphocytes, comprises most of the total endometrial lymphocyte population in the late luteal phase and in early pregnancy (18, 23–25). Often referred to as decidual NK

cells, decidual granular lymphocytes have been shown to exhibit a speciﬁc and distinct surface receptor repertoire. These allow regulation by MHC class I molecules and nonMHC molecules that differ from those recognized by NK cells in the periphery (26, 27). Furthermore, rather than having a primarily cytotoxic function typical of peripheral NK cells, these NK-like cells of the decidua largely serve to support trophoblast invasion, spiral artery remodeling, and vascular growth in the decidua through direct contact with fetally derived placental cells (28, 29). Decidual granular lymphocytes likely derive from endometrial NK cells rather than peripheral NK cells. Based on this understanding, it is unlikely that assessments of peripheral NK cells would lend direct information concerning the function or competency of their decidual counterparts (30). Immune cells that simultaneously exhibit characteristics of NK cells and T cells have been described in the peripheral immune system and within the endometrium and decidua of humans (31, 32). These NKT cells carry a phenotype that suggests innate immune function. Investigations focused on NKT cells at the implantation sites of murine pregnancies have demonstrated that their presence and expansion at this site is mediated by interactions with fetally expressed MHC class I or class I-like products derived from the paternal genome (33). Therefore, the large increase in decidual NKT

FIGURE 1 •Decidual granular lymphocytes •NKT cells •TCRγδ+ cells •Decidual macrophages •Innate lymphoid cells

PopulaƟon Trends

MHC Tolerance Mechanisms

•Th1 cells: Secre on of INF-y, IL-12, IL-2, TNF- β IL•Th •Th2: An body produc on and sec on of IL-10, IL-4, IL-5 secre •Tr •Treg: Secre on of IL-10 •Th •Th17: Secre on of IL-17

Unique Immune Cell PopulaƟons

Cytokine Secretory Profiles

T cell RegulaƟon

GestaƟonassociated Hormonal Control

LigaƟon of Specific Co-sƟmulatory Signals

Estrogen

Progesterone

Shi to Th2 environment

Increase in Th2-type responses, Th1-type cytokine produc on, and leukemia inhibitory factor

Decidual T cells

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Increased Treg and Th17 ac vity during ovula on and fer liza on

Shi to Th2- dominant environment during luteal phase of menstrual cycle

• Expression of CD28, CDL4, PD1, and CTLA-4

MHC class I HLA-G, HLA-E, and HLA-C expression by extravillous trophoblast cells

Surrounding pregnancyrelated cells • Expression of B7-1 and B7-2 on decidual dendri c cells • Expression of B7-H1 and B7H2 by trophoblast cells • Reversed B7-1/2 signaling by decidual stromal cells

Recruitment, enhanced func on and prolifera on of Treg cells

Decrease in CD8+ prolifera on and cytokine secre on Sustaining and expanding Treg cells

Human Chorionic Gonadotrophin

Decrease in IL-17

Increase in IL-27 and IL10

Chemoa ractant for Treg cells

Immune adaptations in the human deciduas. Hyde. Immunologic challenges in reproduction. Fertil Steril 2016.

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cells that occurs during pregnancy may represent a mechanism through which the fetus modulates the maternal immune response to induce tolerance. In addition, because these NKT cells have been shown to secrete much interleukin (IL)-4 (see later section on Cytokine secretion proﬁles), they have been also implicated in the formation of the Th2-dominant environment necessary for successful gestation (34). The peripheral immune compartment and the human reproductive tract contain T cells bearing a TCR comprised of a ab heterodimer (TCRabþ). However, unlike the peripheral compartment, the female genital tract also contains a subset of T cells with a distinctive TCR comprised of a gd heterodimer (TCRgdþ cells), whose population in the decidua increases during early pregnancy (35–37). Unlike their TCRabþ counterparts, TCRgdþ cells may serve in the recognition of non-MHC-restricted antigens as well as support trophoblast invasion and survival (38, 39). Decidual macrophages are responsible for an array of functions at the maternal-to-fetal interface. However, unlike macrophages present in other tissues, these immune cells exhibit a predominately immunosuppressive phenotype, designated M2 polarization, that is characterized by increased IL-10 production and indoleamine 2, 3-dioxygenase activity. Indoleamine 2, 3-dioxygenase catabolizes tryptophan, an amino acid necessary for T-cell activation and proliferation. Before embryo attachment, these decidual macrophages produce leukocyte inhibitory factor and IL-1b, which may help the endometrium become receptive to implantation by regulation of surface glycan structures on epithelial cells (40). In addition, these macrophages play a role in uterine vasculature transformation and fetal immune tolerance (41). One recently described group of immune cells, called innate lymphoid cells (ILCs) (42, 43) may soon be recognized as particularly relevant for our understanding of reproductive immunology. Like other innate immune cells, these cytokine-secreting cells are antigen-independent and have been subclassiﬁed based on their cytokine secretion patterns. Group 1 ILCs produce type 1 cytokines, group 2 ILCs produce type 2 cytokines, and group 3 ILCs produce Th17associated cytokines. In the periphery, group 1 ILCs include NK cells. The presence and function of ILCs in the decidua is still unclear but there is a growing body of literature that aims to better deﬁne these cells (44). The B lymphocytes can present antigen and secrete cytokines, although they are most typically deﬁned by their ability to produce antibodies as a central component of humoral immunity. There are very few B cells present in the human decidua (14) and much less is known about their role at the site of implantation when compared with T cells, dendritic cells, or macrophages. Data from murine studies have demonstrated a complex and nuanced pregnancy-speciﬁc, partial deletion of maternal B cells directed against paternally expressed antigens, which may aid in tolerance of the fetal allograft without simultaneous decrement in pathogen surveillance (45, 46). Similar, but much less marked, numerical changes have been documented in B lymphocyte in the latter parts of human pregnancy, although these may not translate into functional changes (47, 48). Still, the

importance of humoral immunity in human pregnancy maintenance should not be dismissed, as one of the only widely accepted causes of early recurrent pregnancy loss in humans is the autoimmune disease named for the autoantibodies that deﬁne its diagnosis: the antiphospholipid syndrome (14). Although there are relatively few B cells present in the human decidua, there are signiﬁcantly more of these immunoglobulin-producing cells found in the lower female genital tract (endocervix > ectocervix > vagina) and interestingly, in the fallopian tubes (14, 49, 50). Distribution patterns in the lower genital tract can be easily explained by the likelihood of pathogen exposure but that in the fallopian tubes remains unclear. Could nonpathogen directed humoral immunity be particularly important at this site of fertilization and early embryo development? The concept is enticing and identiﬁes an area for future investigation.

T-cell Regulation The TCR on CD4þ T cells recognizes antigen presented by MHC class II molecules on antigen-presenting cells. The MHC class II molecules are particularly important in defense against exogenous pathogens. Helper and regulatory T cells are CD4þ. The typical TCR on CD8þ T cells recognizes endogenous antigens presented on MHC class I molecules at the surface of antigen-presenting cells. These endogenous antigens may be derived from viruses, intracellular bacteria, or result from malignant transformation. In general, gametes and most placental cells are MHC class I and class II negative (51). The major exception is the extravillous trophoblast cell, which, although MHC class II negative, does express the nonpolymorphic nonclassic MHC class I molecules HLA-G and HLA-E, and the more polymorphic classic MHC class I molecule HLA-C (51). This unique MHC expression pattern likely helps to limit classic allorecognition reactions, yet promoting local uterine NK cell-mediated cytokine modulation and maternal vascular remodeling. Antigen presentation has additional layers of complexity. The CD4þ and CD8þ T-cell responses to cognate antigens involve the presence of costimulatory signals in addition to recognition of MHC-complexed antigen by the TCR (52). These costimulatory signals require interaction between a molecule called CD28 on the T cell and B7 molecules expressed on the antigen-presenting cell. Important, if the second signal is not present, the T cell will adapt to tolerate the cognate antigen (53, 54). If the second signal is present, the T cell will proliferate and begin to secrete cytokines. Adding one more layer to the complexity of this interaction is the presence of inhibitors of second signal interactions. Cytotoxic T lymphocyte antigen 4 is expressed on T cells and its expression increases when T cells are activated. This likely serves to control excessive response to antigen. Finally, other B7 family members act as ligands for a molecule expressed on activated T and B cells called programmed death 1 (PD-1) (55). Ligation of PD-1 with its receptor suppresses T-cell activation and promotes T-cell apoptosis or anergy. Ligation can also alter the cytokine secretory proﬁles of allogenic CD4þ T cells in response to VOL. - NO. - / - 2016

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B7 family member expression on human decidual stromal cells (53, 56). As early as insemination, the maternal immune system comes into contact with partner-derived alloantigens. Subsequent trophoblast shedding and continuous trafﬁcking of fetal cells into the mother creates a supply of the same or related alloantigens that could stimulate tolerance reactions by maternal T cells (53). Both decidual stromal cells and trophoblast cells have been shown to display members of the B7 family of ligands; CD28, CDL4, and PD-1 are present on decidual T cells. The B7 family members B7-1 and B7-2 on decidual dendritic cells have been shown to promote the development of a Th2 phenotype (see later section Cytokine secretion proﬁles) upon ligation with responding T cells. A different B7 family member, B7-H1, has been detected on trophoblast cells. The B7-H1 receptor ligation also drives the development of a Th2 phenotype upon ligation to PD-1 on decidual CD4þ, CD8þ, or T regulatory (Treg) cells (53, 54). Other decidual stromal cells have been shown to increase indoleamine 2, 3 dioxygenase production through reversed B7-1/2 signaling after ligation with cytotoxic T lymphocyte antigen 4 on Treg cells (53). Finally, B7-H2 expressed on trophoblast cells interacts with Treg cells to cause an increase in interferon gamma (INF-g) and IL-10 production (54). Both cytokines are necessary for successful gestation. To control abnormally high levels of INF-g that might lead to pregnancy loss or preeclampsia, ligation of either B7-H1 or B7-DC to PD-1 has been shown to decrease additional cytokine secretion and lymphocyte proliferation (55, 56). In summary, these ﬁndings demonstrate the great importance of costimulatory interactions of decidual T cells with surrounding pregnancy-related cells in modulating maternal immune responses.

Cytokine Secretion Proﬁles Subclassiﬁcation of mature T-helper cell phenotypes is largely dependent on the cytokine microenvironment in which naïve T helper (Th0) cells mature and differentiate in addition to their resultant cytokine secretion proﬁles. Th0 cells exposed to INF-g become Th1 cells and Th0 cells exposed to IL-4 become Th2-type cells (57, 58). The Th1 responses are largely inﬂammatory in nature and are associated with the release of IFN-g, IL-12, IL-2, and tumor necrosis factor (TNF)-b. In contrast, Th2 responses are characterized by antibody production and the secretion of the cytokines IL-10, IL-4, and IL-5 (59–61). Other T-helper responses include Treg cell responses, deﬁned by the secretion of IL-10, and Th17 responses, deﬁned by the secretion of IL-17 (62). During the menstrual cycle, there is a distinct increase in Treg and proinﬂammatory Th17 cell activity at the time of ovulation and possibly also at the time of fertilization (63, 64). The localized inﬂammatory-type reactions that are required for implantation (9, 65) must be tightly controlled and simultaneous increases in tolerogenic immune responses occur. When placed in mixed culture with paternal or unrelated peripheral blood mononuclear cells (PBMCs), Treg cells puriﬁed from pregnant women have been shown to suppress secretion of the inﬂammatory cytokine INF-g and

are potent suppressors of the inﬂammatory type 1 (cellmediated) immune responses (66). These cells also suppress IL-4 secretion against paternal antigens during pregnancy (67). The Th1-to-Th2 balance shifts to favor Th2 cells during the luteal phase of the menstrual cycle. At the same time, uterine NK cells dramatically increase in number, becoming the major immune cell population in the decidua (68–70). The number of uterine NK cells continues to increase until the end of the ﬁrst trimester. Together, these changes illustrate the general bias in the female immune system toward an anti-inﬂammatory proﬁle and away from proinﬂammatory Th1 responses that are typical of graft rejection (71). These speciﬁc changes in the female immune system that occur with each cycle could serve to condition the reproductive tract for contact with the foreign paternal antigens present in semen. They could also initiate a tolerizing response toward these antigens that are subsequently present on fetal tissue at the time of implantation (72). The clinical signiﬁcance of these immune players has been well established in several disorders of pregnancy. As arguably one of the most inﬂuential components in establishing tolerance during gestation, insufﬁcient or defective regulatory T cells in the human decidua appear to play a role in the pathophysiology of preterm births, recurrent pregnancy loss, and preeclampsia (73–75). Some investigators suggest that Th17 cells also have important roles in preterm labor, spontaneous abortions, and preeclampsia (76–79). The clinical impact of abnormalities in the activity of decidual NK cells has also been well documented. In cases of spontaneous abortion and recurrent pregnancy loss, decidual NK cells are more cytotoxic than corresponding cells from matched normal pregnancies (78, 80). With regard to the Th1-to-Th2 paradigm, Th1-type cytokines have been shown to be harmful to implanting embryos. Abnormal Th1 immune responses to trophoblast antigens have been documented in women with otherwise unexplained recurrent spontaneous abortion (81–85). Although certainly suggestive, investigations on the roles of T cells and their cytokine secretions in pregnancy loss are blurred by the possibility that some of the changes measured may be a reﬂection of the maternal immune system response to the abnormal and/or failing pregnancy rather than a part of the etiology of the loss (86).

Reproductive Hormones Estrogen (E), P, and hCG are three of the many hormones that play an important role in immune modulation within the female genital tract and the maintenance of the semiallogeneic implanting fetus (87, 88). Compared with the periphery, the concentration of these hormones is signiﬁcantly increased at the maternal-to-fetal interface, which likely contributes to their corresponding effects (89). At high concentrations, Es foster the development of Th2 immune responses in vitro (90–92). In addition, the function and proliferation of Treg cells has been shown to be enhanced by E exposure. Estrogen further enhances Treg cell recruitment to the uterus by stimulating uterine expression of the chemokines CCL3, CCL4, and CCL5 (93). Similar to E, dramatic increases

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in P are observed during early pregnancy and maintained throughout gestation (94, 95). The immune effects of P are complex. This steroid hormone has been associated with Th2-type T-cell responses, increased Th1-type cytokine production, and increases in leukemia inhibitory factor (96–98). In addition, in vitro studies have provided evidence for the suppressive immune effects of this hormone by demonstrating P-related decreases in CD8þ T-cell proliferation and cytokine secretion (99). Progesterone has been shown to be important in sustaining and expanding Treg cells at the time of embryo implantation after their initial E-stimulated proliferation (66). Pregnancy associated protein hormones, such as hCG, also regulate local and systemic maternal immunity. There is a decrease in the expression of proinﬂammatory IL-17 concomitant with an increase in anti-inﬂammatory IL-27 and IL-10 in women supplemented with hCG during IVF (100). The hCG also acts as a chemoattractant that sequesters Treg cells at the fetal-tomaternal interface (101).

FETAL IMMUNOLOGIC CONTRIBUTIONS Remarkably, the developing fetus contributes to the type and extent of immune responses in the female genital tract toward itself as well as toward microbial invaders. During fertilization, sperm must bind to a specialized extracellular glycoprotein matrix, called the zona pellucida (ZP), and then travel through this specialized matrix to fuse with the egg to form a zygote (102). The lectin-like and protein-to-protein interactions involved in human sperm binding to the ZP have been hypothesized to be important for later immune cell recognition of the embryo before blastocyst formation (103). During the pre-embryo stage, there are equal contributions from both maternal and foreign paternal genomes, but shortly after formation, the pre-embryo begins to express paternal MHC molecules (104). The ZP has been shown to protect mouse pre-embryos bearing paternal MHC antigens from destruction by cytotoxic T cells by serving as a physical blockade against rejection of the pre-embryo (102, 104). There is also evidence that by providing a source of paternally derived antigens, fetal microchimerism could induce a donor-speciﬁc type of immune tolerance at the maternal-to-fetal interface (105). Studies conﬁrm that the female immune system recognizes and responds to paternal trophoblast antigens by producing antibodies and T cells in the peripheral blood and decidua that are reactive to fetal human leukocyte antigens (5, 106, 107). The fetus is not a static entity in the immune interactions occurring at the maternal-to-fetal interface nor is it immunologically incompetent (108). As the pre-embryo develops into a fetus, multiple and diverse mechanisms in the intra-amniotic cavity and the neonatal circulation modulate proinﬂammatory immune responses. Fetal immune cells do recognize foreign pathogen and non-self antigens, although during much of pregnancy, naïve fetal T cells have a propensity to differentiate into Treg cells with antigen exposure; a propensity thought to promote tolerance (109). When this response is directed against microbial invaders, it may allow the developing baby to tolerate at least a low level of this immune activation (110). This ability to tolerate local

infection may decrease the likelihood of premature delivery due to infection-controlling immune activation. It could also reduce fetal exposure to toxic immune products necessary for deﬁnitive microbe elimination without promoting the creation of new resistance mechanisms by the offending organism (110). As the pregnancy continues, fetal immune cells will begin to transition toward more adult-type immune cells characterized by more protective immune responses in preparation for delivery, although some fetal-like protolerogenic cells survive in offspring for many years (111, 112).

THE ROLE OF SEMEN AND SPERM Changes in female genital tract immunity that enable allogeneic pregnancy are initiated long before implantation. The ability of both the cellular and soluble components of human semen to alter immune responses within the female genital tract may be critical for the success of human fertilization and reproduction (113–115). Upon entering the female genital tract, human semen and male germ cells face a relatively hostile environment (116). In efforts to ensure safe passage, multiple gene expression pathways are initiated in female epithelial cells upon contact with seminal ﬂuid (117, 118). Of the >700 genes found to be differentially expressed in ectocervical tissue after intercourse, most are involved in the presentation of proinﬂammatory antigens and the expression of cytokines and chemokines that recruit and activate immune cells such as T cells, dendritic cells, and macrophages (117, 118). These semen-induced changes in gene expression and resultant cellular response are known as the leukocyte reaction (117, 119–122). The absence of paternal MHC class I or class II molecules on the human sperm surface serves to bypass the stimulation of speciﬁc histocompatibility-based adaptive responses within the female genital tract (123), yet the environment remains potentially hostile as nonantigenspeciﬁc innate immune mediators have also been activated. As with implantation, the initial inﬂammatory immune response to introduction of male germ cells that need to traverse the genital tract is seemingly counterintuitive and must therefore be nuanced and tightly regulated. The evidence for male-to-female signaling by seminal ﬂuid is vast with studies in porcine, equine, bovine, ovine, canine, and human species. Despite the induction of what at ﬁrst blush would appear to be an ominous immune response for male germ cell invaders, these studies show that exposure to seminal ﬂuid results in higher fertilization rates, increased sperm survival, and improved embryo implantation and development (124). As the leukocyte reaction in the female genital tract commences, the destruction of incompetent or senescent nonfertilizing spermatozoa occurs through processes of apoptosis and phagocytosis that have been termed silent (125, 126). They differ from related processes typical of somatic cells because they occur in the absence of signiﬁcant release of reactive oxygen species or proinﬂammatory cytokines in the local environment. If an infectious agent is present, however, the seminal ﬂuid provides protection for the remaining competent cells from reactive oxygen species that may be generated (125). VOL. - NO. - / - 2016

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Although sperm are MHC negative (123), the deposition of seminal ﬂuid at coitus provides the initial contact of the female genital tract immune system with paternal antigens present on the immune cells, paternal epithelial cells, and cellular debris that are present within seminal ﬂuid. The soluble immune components of seminal ﬂuid then modulate the maternal response to these foreign antigens in such a way that pregnancy can progress when these same antigens are present on the conceptus in a resulting or future pregnancy (127).

induction of an anti-inﬂammatory state in the female genital tract and the recruitment of Treg cell populations to the genital tract. Together, these responses not only serve to modulate responses to paternally derived antigens in semen, but also help prevent rejection of the implanting embryo (129, 139, 140). Investigations focused on the role of PGE2 have uncovered proinﬂammatory and immunosuppressive functions, although the dominant effects appear to be the promotion of Th2-cell responses concomitant with the inhibition of Th1-cell responses (1).

Seminal Fluid and Regulatory T Cells

Seminal Fluid and Dendritic Cells

Perhaps the most signiﬁcant pathway sequence initiated by seminal ﬂuid is the activation and expansion of maternal Treg cells. As discussed previously, elevations in local and circulating E levels at ovulation cause an initial and nonspeciﬁc increase in circulating Treg cells. In conjunction, seminal ﬂuid ‘‘primes’’ this reaction before conceptus antigen encounter by providing the means to expand speciﬁc, paternal antigen-reactive Treg cells through TCR ligation. Only through this mechanism is the suppressive function of Treg cells fully realized (128). First demonstrated in mice, proliferation of Treg cells in para-aortic lymph nodes and responding lymphocytes is markedly increased several days after coitus when females are mated with intact males. This effect is not observed when mating is performed with male mice whose seminal vesicles have been excised (129). Other investigators (130) have provided evidence for the induction of female immune tolerance of seminal ﬂuid by demonstrating a decrease in cell-mediated immunity, a process signiﬁcantly impacted by Treg cells, in similarly designed murine experiments. Demonstrated increases in Treg cell proliferation are not limited to the lymph nodes. Uterine Treg cell populations are also dependent on exposure to seminal plasma (129). In addition, seminal ﬂuid induces uterine expression of messenger RNA encoding the Treg chemokine CCL19, which further increases recruitment of these cells to the uterus before embryo implantation (131, 132). Seminal ﬂuid has effects on the upper reproductive tract that may further affect the quantity and activity of uterine Treg cells. This complex secretion has been shown to increase macrophage populations in the corpus lutea (CL) that, in turn, increase circulating plasma P levels (66, 133). Progesterone is important in both Treg cell differentiation and stability. The CL macrophages are also vital for the remodeling events that must take place within the ovary to maintain the steroidogenic function that supports early pregnancy (66, 134).

The effects of seminal ﬂuid are not limited to those observed in T cells. For the female immune system to mount its robust response to antigens contained in seminal ﬂuid, many immune cells must be present in endometrial tissues during and after ovulation during the period of fertilization and the temporal window of implantation (141, 142). In murine studies, seminal plasma has been shown to induce several dendritic cell chemokines (chemokine [CC] motif ligand [CCL]2, CCL3, CCL5, CCL20, CCL22, and CXCL10) that aid in the after coital recruitment and maturation of additional dendritic cells to endometrial tissues (141, 143). Important, these dendritic cells express markers that identify them as tolerogenic (142). Human in vitro studies have shown that this speciﬁc phenotype appears particularly adept at differential induction of Treg cells that produce and secrete more levels of IL-10 and TGF-b compared with dendritic cells with a nontolerogenic phenotype (144, 145). Such dendritic cells are also important in the clonal expansion of the subset of Treg cells that express TCRs speciﬁc for seminal ﬂuid antigens (145). Interestingly, recent studies in mice have provided evidence that seminal ﬂuid may inﬂuence dendritic and Treg cells by increasing the levels of speciﬁc microRNAs in the female reproductive tract (146). A novel mechanism has also been proposed in which direct delivery of sperm microRNA in microvesicles to the oocyte can impact embryo development and the inheritance of paternal traits (147–149). Last, HLA-G, an unusual MHC class I molecule typically expressed only by extravillous cytotrophoblast cells, has been identiﬁed in human seminal plasma where it has been proposed to induce tolerogenic dendritic cells, aid in the induction of Treg cells, and modulate NK cell immune responses (150–152).

Role of Transforming Growth Factor b and Prostaglandin E2 Transforming growth factor (TGF) b and prostaglandin E2 (PGE2) are arguably the two most important immune modulators in seminal ﬂuid. Both of these key signaling agents act by binding to receptors on cervical and possibly endometrial cells. They have also been shown to play roles in inducing Treg cells (135–138). Transforming growth factor-b is integral to the

Clinical Relevance Given the evidence supporting an important role for seminal ﬂuid in inducing maternal immune changes that support fertilization and implantation, it comes as a bit of a surprise that IVF and artiﬁcial insemination procedures are so successful as each separates sperm cells from the seminal plasma and discards the latter. This shows that seminal ﬂuid is not absolutely required for a successful fertilization event. Rather, the exposure of the female genital tract to seminal plasma appears to most directly impact the ‘‘likelihood’’ of further development of a pregnancy and its overall health. To this point, exposure to seminal ﬂuid has been associated with a

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reduction in certain disease states in pregnant women and improved fetal growth and health (122). Decreased populations or impaired functionality of Treg cells have been described in women with preeclampsia, miscarriage, and primary unexplained infertility (74, 153–156). Women who have had prolonged vaginal or oral exposure to seminal plasma have been shown to have a lower risk of developing preeclampsia than women with signiﬁcantly less exposure (157, 158). Male offspring of seminal plasma-deﬁcient fathers have higher rates of obesity and metabolic syndrome (159). Finally, a recent meta-analysis (160) of seven randomized controlled trials involving patients undergoing IVF demonstrated a statistically signiﬁcant improvement in clinical pregnancy rates (PRs) in those women exposed to seminal plasma at or near the time of oocyte pickup or ET when compared with those patients without exposure to seminal ﬂuid.

FERTILIZATION AND EARLY IMPLANTATION: A ‘‘NEW’’ VIEWPOINT Given the complexity, redundancy, ﬁnesse, and time and location dependency of the immune interactions that support pregnancy maintenance, it should come as no great surprise that theorists have come full circle in their descriptions of these interactions. Fairly recent investigations in painstakingly designed murine models addressing maternal immune responses to paternal antigens have again introduced the concept of immunologic ignorance, at least as it applies to before and peri-implantation events in mice (161, 162). In the setting of an allograft, T-cell antigen recognition can occur in two ways: direct and indirect (163). For direct recognition, T cells in the host directly recognize allogenic MHC/peptide presented on donor cells. This type of recognition appears to be the major contributor to most allograft rejection (164). Indirect recognition involves host T cell recognition of graft-derived antigens displayed by host antigen presenting cells expressing host MHC. Erlebacher et al. (162) have demonstrated that, in mice, allorecognition of paternal antigens only occurred through indirect recognition pathways, that allorecognition through this pathway resulted in speciﬁc deletion of potentially alloreactive T cells, and that allorecognition occurred only after about the middle of mouse gestation. Other factors involved in this delayed allorecognition might include poor MHC expression on gametes and the early embryo, lack of damage to epithelial barriers as sperm and embryo transit the female reproductive tract (limiting danger signals) (8, 165), alloantigen masking (1), and the relatively small amounts of potential alloantigen exposure that are present during early implantation before maternal spiral artery remodeling. Tolerance mechanisms may support and sustain ignorance. Delayed alloantigen recognition explained by immunologic ignorance was supported by another study published at about the same time (161) demonstrating that mice were ignorant of paternal antigen when exposed through intravaginal insemination. This state of speciﬁc ignorance to paternal alloantigen persisted from the time of semen exposure through estrous and early implantation. It was not

present if the paternal antigen was administered SC. The demonstrated importance of E to this process reinforces the concept that timing and location of antigen exposure may be critical. Again, several other factors may have been involved, including alloantigen masking (1, 166), poor MHC expression on gametes, silent sperm phagocytosis and limited danger signals, and the multiple immunosuppressive properties of human seminal ﬂuid. It is worth mentioning that some investigators have attempted to explain maternal tolerance of the fetal allograft using paradigm-shifting descriptions of the mechanisms underlying immune responses. For example, proponents of the danger model (165, 167) posit that the initial event signaling an immune response is not the discrimination of self versus non-self but rather the recognition of tissue damage or cellular stress that releases a danger signal. This adds a third, albeit initiating, signal to the two signal theories of immune recognition relying on a combination of self non-self recognition and a second signal from T helper cells. In the two signal models, the helper T cells themselves require antigen recognition and a costimulatory signal or they will die. In the danger model, T-cell recognition of antigens in the absence of danger signals will die. Only antigen recognition in the local environment of tissue damage signaling danger will be fully activated. Cells undergoing programmed cell death (apoptosis) do not release danger signals. Like more classic models of immune response, the danger model can be used to explain many, but not all, of the alloimmune challenges of human fertilization and implantation. For instance, although millions of sperm enter the female genital tract after intercourse, nonfertilizing sperm die by apoptosis rather than necrosis. Therefore, in the absence of tissue damage within the female mucosal tract, no danger signals are generated and no immune response against alloantigens in semen occurs. The existence of alternate and well-reasoned models for immune responses speak directly to the fact that experimental data surrounding the immunology of eutherian pregnancy is so complex that a single simpliﬁed model presently appears insufﬁcient. In conclusions, discussions of the immune interactions surrounding the maintenance of human pregnancy invoke multiple, complex, overlapping, and redundant mechanisms. There remain inconsistencies within the large volume of available literature that can frustrate the reproductive immunologist. These may arise from several sources. The impact of certain mechanisms may be time and location speciﬁc. Most must be balanced by the necessity to retain appropriate immune responses to pathogen and nonpathogen related local immune insults. Some pregnancy-speciﬁc immune changes may be initiated to address differing levels of antigen exposure, such as those occurring during implantation of a relatively small embryo versus those encountered throughout pregnancy during placental syncytiotrophoblast turnover. Some may be particularly difﬁcult to study in humans, including those interactions occurring at the site of implantation and during the ﬁrst steps of placental development when an unusual form of syncytiotrophoblast acts as the invading edge of fetally derived tissues. Because the latter interactions are particularly difﬁcult to study in humans for logistical and ethical reasons, some of our VOL. - NO. - / - 2016

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insights may derive only from animal studies, many of which may have limitations due to the high degree of placental invasion noted in humans when compared with most model species. The complexity of general immune responses may presently defy explanation using a single model. For these and many other reasons, our understanding of the intricacies of these interactions continues to be regrettably incomplete. The challenge is great. Our response to this challenge must remain focused and robust.

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Immunologic challenges of human reproduction: an evolving story

Immunologic challenges of human reproduction: an evolving story

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