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MHC Molecules of the Preimplantation Embryo and Trophoblast

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The mechanisms of protection of the allogeneic fetus from the maternal immune response during pregnancy remain mysterious more than fifty years after the paradox of maternal tolerance was first raised by Peter Medawar. Preimplantation embryos express paternal antigens early in development. After implantation, placental tissue is derived from both maternal tissue and paternal-antigen expressing fetal tissue that is in intimate association with and bathed in maternal blood. There appears to be a key role for an unusual subset of major histocompatibility complex (MHC) Class I proteins of both maternal and paternal origin in the mediation of tolerance at the maternal/fetal interface and in the control of preimplantation embryonic growth rate. This subset of MHC products is composed of two nonclassical MHC Class Ib proteins, HLA-E and HLA-G in combination with a classical MHC Class Ia protein, HLA-C. This chapter reviews the history of the discovery of the major histocompatibilty complex Class I genes and the elucidation of the biological role of the proteins encoded by these genes in the immune response and in reproduction. MHC genes have also been implicated in reproductive choice and nurturing behaviors. We hypothesize that the vertebrate immune system derived from ancestral recognition systems driven by reproductive requirements, and was later coopted for immune recognition under additional evolutionary pressures. The complex interactions of MHC Class I proteins with components of both the innate and the adaptive immune systems in the context of the preimplantation embryo and the trophoblast of early pregnancy are described in detail, as are the difficulties inherent in studying these systems. Finally, potential future directions of research and the need for new model systems to study both preimplantation embryos and the maternal/fetal placental interface are discussed.


The acquired immune system, also known as the adaptive immune system, exhibits signature attributes of pathogen specificity and memory response. It emerged abruptly and mysteriously in the vertebrate lineage some 500 million years ago.1 Antigen-recognizing T and B cell receptor genes, combinatorially rearranged by recombinase activating gene (RAG) enzymes, together with antigen-presenting genes of the major histocompatibility complex (MHC) apparently appeared simultaneously in jawed vertebrates. These characteristic components of the acquired immune system coexist in the earliest jawed fishes but are absent in jawless hagfish and lamprey. There is no conclusive evidence of the evolution of transitional molecules in the 50 million years between the divergence of the jawless and jawed fishes from their last common ancestor. Over time the functions of the acquired immune system in vertebrates have become inextricably blended with those of the innate immune system. The first goal of this review is to discuss the evolution of the MHC with respect to its role in reproduction. We will propose the hypothesis that the vertebrate immune system derived from ancestral recognition systems driven by reproductive requirements, and was later coopted for immune recognition.

The function of the MHC in graft rejection was first defined by Gorer2 and Snell3 in studies of the role of the mouse histocompatibility (H-2) locus in rejection of transplanted ‘nonself ’ tissue. The equivalent human leucocyte antigen (HLA) locus was first identified by Dausset in 1958.4 What was at first defined as a major histocompatibility genetic ocus” is now known to encompass many genes, resulting in the present day use of major histocompatibility “complex” to describe this genetic region. For many years the biological function of the MHC was unknown. The groundbreaking discovery, by Doherty and Zinkernagel,5 that T-cells recognize peptide only when presented in the context of an MHC molecule, defined an immunological function for MHC molecules. Crystallization and X-ray diffraction studies in the laborarsk Strominger and Don Wiley provided a molecular understanding of peptide presentation first by Class I MHC molecules6 and later by Class II molecules.7

The MHC is a four megabase continuous region of DNA located on chromosome 6 in humans and chromosome 17 in the mouse. The complex is composed of three subregions encoding MHC Class I, Class II and Class III genes which in turn encode Class I, Class II and Class III proteins. Class I MHC genes and proteins are the main subject of this review and are discussed in detail later. Class II MHC genes are very polymorphic in human populations, and their protein products are expressed primarily on “professional” antigen-presenting cells: macrophages, dendritic cells and B-cells. Class II proteins present 13-18 amino acid peptides derived from extracellular pathogens to CD4+ T helper cells and are important in the priming and maintenance of the humoral immune response. Class III MHC genes are more conserved and encode a variety of secreted proteins, some of which play a role in antigen processing, in inflammatory responses and in the complement cascade. Class II and Class III MHC genes and proteins are not discussed in detail in this review.

Class I MHC proteins are used by cells to present 8-11 amino acid intracellularly-derived peptides to CD8+ T cytotoxic cells and to natural killer (NK) cells. Class I MHC molecules consist of a trimeric complex of three noncovalently bound components: the MHC Class I heavy (alpha) chain encoded in the MHC, the small antigenic peptide which is being presented to immunocytes, and beta2 microglobulin (β2m), which is encoded in chromosome 15 in humans and chromosome 2 in the mouse. Displayed peptides may be endogenous cellular peptides (self peptides) or peptides derived from intracellular pathogens (nonself peptides). Peptide-MHC Class I -β2m complexes (pMHC) interact with the T cell receptor (TCR) on CD8+ T cells of the acquired immune system, and with multiple receptors on natural killer (NK) cells of the innate immune system. MHC Class I genes are subdivided into “classical” Class Ia genes and “nonclassical” Class Ib genes. The human Class Ia genes, HLA-A, -B and -C, are highly polymorphic and are expressed on the surface of almost all nucleated cells. HLA-A and —B genetic loci were first identified by van Rood using human pregnancy serum containing alloantibodies against fetally expressed paternal histocompatibility antigens;8 his discovery led to significant advances in kidney transplantation because these reagents could be used to tissue-type donors and recipients. A decade later the third locus, HLA-C, was identified. These products are notable for lower levels of expression at the cell surface than other class Ia counterparts. 9 Nonclassical Class Ib genes HLA-E, -F and G were initially defined in comparison to Class Ia genes by reduced polymorphism, restricted tissue expression and unknown function. Class Ib genes and their products remain somewhat enigmatic, but recent studies have shown that they can exhibit polymorphism and either tissue restriction or more ubiquitous expression.10

Polymorphism in MHC Class I genes is most evident in their peptide binding region. Such polymorphism is generated by amino acid-altering mutations in the MHC genes and is sustained by balancing selection during evolution. Heterozygosity of MHC alleles in an individual is believed to improve immune surveillance by increasing the array of peptides that can be presented to the immune system, thus enhancing protection from disease. There are intriguing data suggesting that MHC Class I genes also play a role in mate selection and other behaviors that favor increased MHC heterozygosity in offspring.11 MHC genes are closely linked on the chromosome and alleles tend to be inherited in sets or haplotypes, one from each parental chromosome. The MHC alleles are codominantly expressed, so each individual expresses both paternal and maternal MHC gene products. In the case of Class I proteins, an individual is self-tolerant to endogenously presented peptides because of an essential and rigorous process of negative and positive selection occurring in the thymus, supplemented by peripheral mechanisms inducing tolerance or anergy in potentially autoreactive T cells.12

In 1953 Peter Medawar first raised the paradox of maternal tolerance to the paternal MHC in the fetus during pregnancy,13 but to this day mechanisms of protection of the fetus from the maternal immune response are not fully understood (see Introduction). Of particular interest to this review is whether or not Class I MHC proteins are expressed in preimplantation embryos and in the trophoblast. The interactions between Class Ia and Class Ib molecules and among all Class I molecules and components of the adaptive and innate immune systems during early pregnancy are complex, redundant and as yet poorly understood. The system exhibits many inherent qualities that promote slow progress in research leading to an improved understanding of the role of MHC Class I molecules in early pregnancy. For instance, in humans there are technical difficulties in obtaining samples during temporally and spatially restricted developmental stages of pregnancy. The unique extent of placental invasion in humans makes comparison with other species of somewhat limited relevance. Information on MHC Class I expression in human embryos is sparse given the moratorium on federal funding of such work in the United States. Therefore reliance on animal models has been mandatory, even though the results may not be fully applicable to humans. The second goal of this review is to discuss MHC Class I protein expression and possible function in preimplantation embryos and in the trophoblast, with respect to protection of early embryos from rejection by the maternal immune system. The main emphasis will be on human embryos, with some reference to data from animal models where such comparisons are informative.

Evolution of the MHC

The dearth of organisms providing clues to the transitional development of the MHC during the divergence of the jawless and jawed fishes makes discussion of the selective pressures driving development somewhat speculative. There is indirect evidence for the existence of a MHC-like molecule in a colonial invertebrate urochordate. Botryllus schlosseri, a tunicate sea squirt, expresses a gene coding for a protein remarkably similar to vertebrate CD94, a receptor expressed in natural killer cells which binds MHC Class I in mice and humans.14 Botryllus colonies that meet or are placed in contact with each other will either fuse together or develop cytotoxic lesions in an allorecognition reaction. This allorecognition is mediated by a single highly polymorphic and codominantly expressed fusibility/histocompatibility (Fu/HC) locus. Colonies that share a Fu/HC allele will fuse forming a chimera with a joint vascular system, while colonies not sharing an allele will undergo rejection. Fu/HC loci are not orthologous to vertebrate MHC loci but clearly exhibit similar characteristics. Fu/HC may be an ancestral MHC molecule, or both molecules could have evolved from a common ancestor. It is not yet known if the Botryllus CD94 homolog interacts with Fu/HC proteins, but it is upregulated during allorecognition responses and was identified in a differential display PCR screen comparing RNA extracted from isolated colonies with RNA from colonies undergoing allorecognition reactions.14

Gametogenesis involving circulating germ-line progenitor cells can occur in Botryllus colonies after fusion, and germ cell ‘parasitism’ can occur in fused colonies. In some cases one colony can be completely resorbed by the other, yet the surviving germ cells may have derived from the resorbed colony. The maintenance of a highly polymorphic Fu/HC system combined with fusibility only with colonies sharing an allele ensures that parasitic germ cells requiring somatic resources in a fused colony at least come from a sibling colony.15 Vertebrates do not undergo natural transplantation processes, with the exception of pregnancy, where the semi-allogeneic fetus can be considered in that light. The vertebrate immune system may thus have derived from ancestral recognition systems driven by reproductive requirements, and later modified under additional evolutionary pressures to evade pathogens.

Gene families characteristic of the human MHC-linked paralogy region (so called MHC anchor genes) appear to have been assembled and linked in the cephalochordate Amphioxus prior to the origin of vertebrates and in the absence of adaptive immune system genes.16,17 These conserved anchor genes can be considered a “proto-MHC” present in Amphioxus, which is believed to represent the ancestral genome before vertebrate tetraploidization.10 This framework hypothesis18 suggests that the nonconserved Class I genes then expanded in permissive sites within the highly conserved anchoring framework genes of the MHC. It is clear that, at least in mammals, orthology is maintained only by the nonClass I MHC genes in the MHC complex.10

MHC and Reproductive Behavior

MHC Class Ia genes play an unequivocally central role in the immune response, but have also been shown to influence mate selection resulting in increased MHC heterozygosity of progeny. MHC-driven mate choice based on odor cues has been documented in mice,19 and more controversially in humans.20 There are three extant and not mutually exclusive hypotheses for MHC-dependent mating preference: augmented immune surveillance by increasing the array of peptides that can be presented (heterozygote advantage), improved defense against fast-evolving parasites (the Red Queen hypothesis), and avoidance of inbreeding.11 The relationship between MHC genetic composition and behavior is complex, involving selection for kin recognition in addition to MHC-disassortative mate choice. Female mice, which preferentially select mates with MHC alleles different from their own, will nurse each other's pups in communal nests but appear to prefer nesting partners sharing their MHC alleles.21 MHC-based odortypes also aid in reciprocal recognition by mothers and pups, even if the pups have been cross-fostered with an MHC-dissimilar female.22 Intriguingly, subsequent MHC-based mate selection preferences can be altered by cross-fostering pups,23 indicating that early learning experiences of the MHC environment are important for subsequent inbreeding avoidance as well as maternal nurturing behavior.

Odor detection of classical MHC genes provides chemical cues for recognition, evoking neural activity in the main olfactory bulb (MOB) of the mouse brain and resulting in measured behavioral responses. Indeed, a cluster of polymorphic olfactory receptor genes has been identified at the distal end of the mouse MHC and shares a history of coduplication with MHC genes.24 The MOB recognizes volatile chemical cues. Neural responses to volatile cues are seen even in the absence of the vomeronasal organ (VNO) that detects nonvolatile pheromones and activates neurons in the accessory olfactory bulb (AOB).25

Mammalian pheromones elicit both long-term effects on the neurendocrine status of a recipient animal and short-term effects on behavior. Activation of the VNO neurons is thought to trigger innate or “hardwired” behaviors.26 Investigation of mouse vomeronasal receptors has begun to dissect out the molecular mechanisms of pheromone signaling from the VNO to the AOB and to relate them to specific social behaviors. There are two independent families of VNO-specific receptors—the V1R family and the V2R family—expressed in spatially segregated populations of neurons. The M1 and M10 groups of MHC Class Ib molecules have now been shown to form complexes with β2m and the V2R receptor family subset. Mice that are deficient in β2m and thus cannot express stable pMHC complexes on the surface of cells, can be discriminated from β2m positive littermates by odortype.27 Also, β2m knockout mice exhibit deficits in pheromone induced male-male aggressive behavior.28 Female triple-knockout mice deficient in murine Class Ia molecules H-2Kb, H-2Kd and β2m exhibit significant deficits in maternal nurturing behavior, leading to reduced litter survival (personal observation, D. Gould and D. Schust).

TRP2, is a putative ion channel expressed in the VNO and potentially involved in signal transduction pathways triggered by vomeronasal receptor binding. Mice deficient in TRP2 show an absence of VNO sensory activation by pheromones in urine. Pronounced behavioral effects result, with male TRP2-deficient mice failing to display normal aggressive responses to intruder males. TRP2-null males are also apparently unable to gender-discriminate; they display courtship and mounting behavior equally toward both males and females.29 Lactating TRP2-deficient females also exhibit an unusual lack of aggression against intruders.30 Current evidence suggests that the VNO became vestigial in the common ancestor of Old World monkeys and apes, and it has been proposed that pheromone signaling may have been replaced by color vision in higher primates and humans.31 The M1 and M10 MHC Class Ib gene families, associated with β2m and V2R receptors in the VNO of rodents, are not represented in the human genome.10

Different MHC Class Ia and Class Ib genes are expressed in unique subsets of neurons in the central nervous system (CNS), suggesting functional diversity among the genes expressed in this tissue. Neuronal MHC Class I expression corresponds temporally and spatially with well-established areas of activity-dependent development and plasticity in the mouse CNS.32 These unexpected roles of Class I genes in the CNS, MOB and AOB suggests that MHC Class Ia and Ib gene interactions may originally have evolved as a genetic incompatibility system driving reproductive and rearing behavior, and subsequently coopted for immune recognition. Sexual selection and reproductive fitness are, after all, selective pressures as powerful as the ability to resist infection33,34

MHC Class I in Preimplantation Embryos

In humans, fertilization of the oocyte by spermatozoa typically occurs in the distal portion of the fallopian tube, the tubal ampulla. Binding and fusion of sperm and oocyte membranes at fertilization promote two major events: oocyte changes that block polyspermic fertilization and resumption of oocyte meiosis, with release of the second polar body. In vitro, male and female pronuclei form at a median of 8 hours post-insemination and can be reliably identified microscopically approximately 18 hours after fertilization.35 By 24 hours post-fertilization, pronuclear membranes have disappeared, parental chromosomes have intermingled and the first cellular division occurs. The stages of preimplantation embryo development, which are similar in mouse and human, are depicted in Figure 1. The preimplantation period lasts 4-5 days in mice and 5-7 days in humans.

Figure 1. Preimplantation embryo development.

Figure 1

Preimplantation embryo development. Stages of preimplantation embryo development are similar in mouse and human. The preimplantation period lasts 4-5 days in mice and 5-7 days in humans. Early cellular doubling divisions occur without a perceptible increase (more...)

The initial cell divisions occur in the absence of messenger RNA synthesis, and appear to be driven exclusively by maternal cytoplasmic signals, an occurrence termed the “maternal legacy”.36 These signals are hypothesized to originate within maternal mitochondrial DNA, which does replicate during early embryonic cell divisions. The point at which the paternal genome is activated to undergo transcription is called zygotic gene activation (ZGA).37 ZGA in embryos is first detected 2-3 days after fertilization when the embryo consists of 4 to 8 cells.36 In the mouse, ZGA occurs earlier, at the two-cell stage.38 It is important to note that early cellular divisions occur without a perceptible increase in embryo size and each individual cell within the embryo is totipotent until at least the 8 cell stage. Removal of a single cell or blastomere before this stage can occur without disruption of embryonic development.39,40 Continued cell divisions occur while the embryo moves proximally within the oviduct toward the intrauterine cavity. By the time this cavity is reached, the developing embryo has completed the 16 cell, solid morula stage and has progressed to the cavitating 32-64 cell, blastocyst stage. Although differential gene expression has occurred earlier, it is not until the blastocyst stage that two types of cells can be easily differentiated microscopically. At the blastocyst stage, the developing embryo has an identifiable, fluid-filled cavity, called the blastocoel, a surrounding layer of trophectoderm that will contribute to formation of the placenta, and an inner cell mass that will form the fetus and some extra-embryonic tissues. Just prior to implantation in the uterus, the blastocyst ‘hatches’ from the zona pellucida that has surrounded it since the oocyte stage.

Initial studies of MHC Class Ia and Class Ib mRNA and protein expression in mouse preimplantation embryos reported the absence of MHC Class I antigens before mid-gestation.41,42 As more sensitive techniques became available, expression of mRNA and protein for Class Ia43-45 and Class Ib46-49 molecules was detected on all mouse preimplantation stages from oocyte to blastocyst. Class I MHC proteins on mouse embryos are capable of functional interactions with T cell receptors, and cytotoxic T lymphocytes (CTL) can recognize and kill Class I-expressing embryos after removal of the zona pellucida.50 This suggests that the zona pellucida may play an immunoprotective role during early embryonic development.

Early studies on human preimplantation embryos also reported the absence of MHC gene expression.51,52 There are, to date, no reports of MHC Class Ia HLA-A, -B, or -C mRNA or protein expression in human preimplantation embryos. Evaluation of mRNA expression for Class Ib genes HLA-E, and -F using RT-PCR in a sample of 108 spare day three human preimplantation embryos from 25 couples indicates that HLA-F is not transcribed while 84% of the embryos were positive for HLA-E mRNA.53 Three studies of HLA-G mRNA expression in almost 300 embryos from oocyte to blastocyst stage report that 40 to 90% of the embryos were positive for HLA-G mRNA.53-55 One study using eleven embryos reported no HLA-G message expression,56 indicating that there may be marked variability in HLA-G mRNA expression in embryos and that sample size may be particularly important. The presence of HLA-G protein in preimplantation embryos has also been reported, and despite varying expression levels, HLA-G mRNA expression intriguingly correlated with a faster cleavage rate of the embryos.54

Soluble isoforms of HLA-G protein have been identified in supernatants from human embryos cultured in vitro. Preliminary reports indicate that the presence of soluble HLA-G in tissue culture supernatant may correlate with more successful pregnancy outcome.57-59 Human embryos fertilized in vitro at the same time exhibit a range of rates of development and, notably, embryos that develop faster exhibit preferential survival. The rate of development is one of the characteristics used in the evaluation of embryos (a component of the embryo quality score) for transfer to recipient mothers during in vitro fertilization procedures.60 These observations echo the phenotype of the Ped (preimplantation embryonic development) gene in mice, which influences the rate of preimplantation embryonic development and subsequent embryonic survival.

Qa-2, The Preimplantation Embryo Development (Ped) Gene Product

Qa-2, the mouse Ped gene product, is a MHC Class Ib protein with a defined function in regulation of preimplantation embryonic development. Embryos expressing Qa-2 exhibit a faster cleavage rate during preimplantation development. The effect is independent of the maternal environment as Qa-2 positive embryos also develop faster in vitro.61 Removal of Qa-2 using enzymatic or antisense microinjection techniques slows the rate of development,62,63 while microinjection of Q7 and/or Q9 DNA encoding the Qa-2 protein increases the embryonic cleavage rate.64 Beyond the preimplantation stage of development, the Ped gene also confers survival advantage to term.65 Postnatally, Qa-2 positive mice exhibit enhanced birth and weaning weights.66 Studies are ongoing to determine whether Qa-2-expressing mice have additional survival advantages as adults. Warner and Brenner include a comprehensive overview of the Ped gene and the search for its human homolog in their extensive review of the genetic regulation of preimplantation embryo survival.67

HLA-G Is the Proposed Human Functional Homolog of Mouse Qa-2

HLA-G and Qa-2, like all mouse and human Class I proteins, are structurally similar and interact with receptors of the acquired and innate immune systems. The receptors of the innate immune system in mice, while exhibiting similar functions to the human NK receptors, derive from different gene families than in the human in a striking example of convergent functional evolution. Analysis of mouse-specific gene clusters expanded after divergence from the mouse-human common ancestor revealed that reproduction and host defense and immunity are major functional themes of the expanded gene clusters in the mouse, indicative of strong evolutionary pressure.68 Concordant with the roles of MHC Class Ib genes in both immunity and reproduction discussed in this chapter, there is evidence that these are intertwined and fundamental processes subject to selective pressures at the species level.

Orthologous genes have been defined as genes that are related by vertical descent from a common ancestor and encode proteins with the same function in different species.69 Orthologous relationships of MHC Class I genes have not been found among different mammalian orders where the number of Class I genes is highly variable. Convergent evolution can, however, result in nonorthologous genes encoding proteins with similar functions as is seen in the case of HLA-E in the human and Qa-1 in the mouse10 and HLA-G in the human and Qa-2 in the mouse.70 Similarities noted between HLA-G and Qa-2 and summarized in Table 1.71 suggest that HLA-G is the most likely human functional homolog of the mouse Ped gene despite one apparently major difference between the molecules, namely their method of insertion into the cell membrane.

Table 1. Comparison of HLA-G and Qa-2, the Ped gene product.

Table 1

Comparison of HLA-G and Qa-2, the Ped gene product.

Qa-2 protein is glycosylphosphatidylinositol (GPI)-linked in the outer leaflet of the phospholipid bilayer of the cell membrane. GPI linkage occurs as a post-translational modification of proteins in the endoplasmic reticulum, and the presence of a GPI ‘tail’ targets proteins to detergent-insoluble membrane domains enriched in glycosphingolipids and cholesterol. The lipid domains or ‘rafts’ seem to correspond to distinct membrane microdomains with a more ordered liquid phase than the bulk cell membrane. Although they lack a transmembrane domain, ligation or clustering of GPI-anchored proteins on the cell surface can initiate signal transduction through activation of acylated kinases constitutively present in the cytoplasmic leaflet underlying the rafts.72 HLA-G is not a GPI-linked molecule, but unlike Class Ia MHC proteins that contain a standard hydrophobic transmembrane domain and a 30-40 amino acid cytoplasmic domain, HLA-G has an abbreviated six amino acid cytoplasmic tail. A diagram comparing Qa-2 and HLA-G is shown in Figure 2.

Figure 2. Comparison of the structure of HLA-G and Qa-2.

Figure 2

Comparison of the structure of HLA-G and Qa-2. The extracellular domains of the proteins are similar consisting of a trimer complex of three noncovalently bound components: the MHC Class I heavy (alpha) chain containing alpha 1, alpha 2 and alpha 3 domains, (more...)

Functional homology of Qa-2 and HLA-G implies that the short cytoplasmic tail of the HLA-G molecule is equivalent to the GPI-linkage of Qa-2 in permitting HLA-G to localize to lipid rafts, and invoke raft-associated signaling pathways. Alternative use of GPI-anchored versus short cytoplasmic-tailed protein homologs in rodents and man is not without precedent in the literature. It has been reported that in carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a short cytoplasmic domain isoform in rodent leucocytes has been functionally replaced by a GPI-linked isoform in the human.73 Preliminary investigation of the association of HLA-G with lipid rafts indicates that the molecule can indeed associate with raft microdomains in the cell membrane.71 Figure 3 contains immunofluorescence images showing colocalization of Qa-2 and of HLA-G with lipid raft marker GM1 in mouse EL-4 lymphoma cell line and human choriocarcinoma cell lines respectively. Lipid rafts are labeled with Cholera Toxin β subunit conjugated with Alexa Fluor 594 (red). Anti-Qa-2 and anti-HLA-G are labeled with a secondary antibody conjugated with Alexa Fluor 488 (green). The overlay panels show, in yellow, colocalization of Qa-2 and of HLA-G with lipid rafts. Molecules interacting with Qa-2 or HLA-G in mouse or human preimplantation embryos respectively have not been defined, although intensive research is underway to identify Qa-2 interacting molecules in the mouse model. Initially focusing on molecules known to interact with Qa-2 in the immune system, this work does not preclude the existence of novel associations/functions during preimplantation development.

Figure 3. Qa-2 and HLA-G colocalize in lipid rafts.

Figure 3

Qa-2 and HLA-G colocalize in lipid rafts. MHC class Ib species are found in lipid rafts in mouse and human. Immunofluorescence colocalization of Qa-2 with lipid rafts in the mouse EL-4 lymphoma cell line (top row) and of HLA-G with lipid rafts the the (more...)

Implantation and MHC Class I in the Trophoblast

Implantation of the embryo in the uterus is a complex process, controlled by both maternal and embryonic signals (reviewed in refs. 74,75). During this process, the embryo becomes completely embedded within the maternal intrauterine endometrial lining, which has prepared for implantation by transforming into a metabolically-active, secretory entity called the uterine decidua (fig. 4). During implantation, trophectoderm cells begin to differentiate into the cellular subtypes that will characterize the mature human placenta. The human hemochorial placenta is comprised of a mass of arborized placental cotyledons (villae), derived from embryonic precursors and bathed in maternal blood. Maternal blood flows into the space between the maternal decidua and the placental villae (the intervillous space) via low resistance, high flow vessels branching from the maternal decidual spiral arteries. The core of each placental cotyledon is traversed by fetal vessels. These vessels are, in turn, surrounded by layers of trophoblast cells. The inner layers of cells are called cytotrophoblast cells (CT). The outer layer of the placental villae is coated by a syncytium of fused, multinucleated cells, called the syncytiotrophoblast (ST) (see Chapter by Guller et al).

Figure 4. Human placenta microarchitecture.

Figure 4

Human placenta microarchitecture. Fetal derivatives in the placenta consist of fetal vessels and placental cotyledons (villae). Villae consist of fetal vesels surrounded by cytotrophoblast cells (CT). Covering the cytotrophoblast cells is a multinucleated (more...)

Most placental villae are free-floating within the intervillous space. They originate from fetal tissues and are wholly bathed in maternal blood. A subset of anchoring villae completely traverses the intervillous space and attach directly to the maternal decidua. Within these structures, a subpopulation of extravillous cytotrophoblast cells differentiates into an invasive phenotype. Extravillous cytotrophoblast cells differ from their villous counterparts in the expression of cell surface molecules including MHC76 and proteinase products.74 They aggressively invade into the maternal decidua, here coming into direct contact with maternal decidual lymphocyte subpopulations. A subpopulation of the extravillous trophoblast cells (EVT) will invade into the maternal vasculature itself, replacing some of the muscular and supporting cells within the wall of the decidual vessels.77,78 These endovascular trophoblast cells (ET) are felt to be important in transforming decidual vessels into low resistance, high flow structures, thereby protecting maternal-to-fetal nutrient transfer. The intimate apposition of maternal and fetal tissues and the continuous exposure of fetal tissues to circulating maternal blood are at the core of the immunological paradox first posed by Medawar—how are the embryo and the placental embryo-derived tissues expressing paternal MHC antigens protected from the maternal immune response?

Trophoblast cells are one of the few physiological cellular populations in the human body that lack typical MHC Class Ia (HLA-A and HLA-B)79 and MHC Class II products.80,81 Syncytiotrophoblast and villous cytotrophoblast cells are completely devoid of these products, and some investigators promote this as important in maternal tolerance to the fetal allograft. The invasive extravillous cytotrophoblast and endovascular trophoblast cell subsets, however, express a unique subset of MHC Class I products: HLA-C, HLA-G and HLA-E.82-86 The function of these cell surface molecules remains enigmatic, though many theories have been promulgated. The vast majority of theories concern direct and indirect mechanisms that alter adaptive and/or innate immunity; however, one intriguing series of investigations suggest that the expression by fetus-derived cells of any or all of the trophoblast MHC Class I products could promote essential decidual and vascular invasion.87 In support of this, alterations in trophoblast expression of HLA-G has been linked to disorders of placental invasion, including preeclampsia.87,88

In considering the function of trophoblast Class I species, it may be instructive to discuss important ligands for Class I products that are present on the surface of resident decidual lymphocytes. Like lymphocyte populations at other mucosal sites,89 decidual lymphocyte subpopulations differ dramatically from those typical of the peripheral immune compartment.90,91 The human endometrium is normally populated by T cells, macrophages, NK-like cells, and a very limited number of B cells,92 but during the late luteal phase and in early pregnancy, nearly 70 to 90% of endometrial lymphocytes are believed to be variants of natural killer cells.93-95 These unusual cells have been variably called decidual granular lymphocytes (DGLs), large granular lymphocytes (LGLs), and decidual natural killer cells.

Natural killer cells are a part of the innate immune system, poised for rapid, antigen-independent recognition of the absence of MHC Class I molecules,96 the “missing self ” hypothesis. The ligands on the surface of NK cells recognize MHC Class I products that can be either inhibitory or activating (reviewed in ref. 97). NK cell receptor categorization is complex and differs among species. In humans, NK receptors fall into two major subcategories: immunoglobulin-like, killer inhibitory receptors (KIRs), and lectin-like heterodimers comprised of CD94/NKG receptor complexes. KIR molecules of both the activating and inhibitory subtypes have been shown to recognize HLA-C locus molecules,98 while both activating and inhibitory CD94/NKG receptor complexes recognize HLA-E molecules.97,99 HLA-G can also interact directly with diverse NK receptors, with some outcomes dependent on the activation state of the cell.100

Interactions between trophoblast Class I species may allow HLA-G to indirectly control NK cell function in addition to its direct interactions. To this point, HLA-E species have been shown to utilize signal sequence-derived peptides as their essential “antigenic” component allowing stable cell-surface expression of the trimolecular Class I complex.101-103 Peptides derived from the HLA-G leader sequence are particularly suited to binding within the HLA-E antigen-binding cleft so that generation of the leader peptide during HLA-G synthesis could control cell surface expression and receptor interactions of HLA-E in the placenta. The binding affinity of HLA-E for the inhibitory receptor CD94/NKG2A is usually higher than its binding affinity for the activating receptor CD94/NKG2C. However, the HLA-G leader sequence peptide complexed with HLA-E binds activating receptor CD94/NKG2C with an affinity high enough to trigger an NK cell response (reviewed by Moffett-King34). Coexpression of HLA-E and HLA-G in the invasive extravillous and endovascular trophoblast cells therefore suggests that either HLA-G itself interacts with an inhibitory receptor in NK cells, or both molecules act coordinately with HLA-C expressed in the same cell to regulate interactions with inhibitory and activatory NK receptors. HLA-C products exhibit considerable polymorphism, but have a relatively short half-life at the cell surface,86 which may limit their efficacy in antigen presentation. The short half-life of HLA-C on the cell surface is also in marked contrast to the unusual stability of HLA-G on the cell surface of the same cell populations.104 HLA-C has, however, also been reported to be the dominant Class I molecule preventing killing by NK cells. Moreover, it binds to KIR inhibitory molecules with association and dissociation rates that are among the fastest kinetics seen in immune system interactions.105 The rapid kinetics of HLA-C interactions with KIR may be sufficient to counteract the short half-life on the surface of the cell. KIRs specific for HLA-C are expressed by a higher percentage of uterine NK cells than peripheral-blood NK cells in pregnant women, suggesting that NK-cell specificity is skewed towards HLA-C in the uterus,34 just as endometrial lymphocytes in early pregnancy are skewed towards NK cells.

CD94/NKG receptors are conserved between rodents and primates, but the KIR receptor families evolved in primates after the separation of rodent and primate lineages. In mice, the equivalent receptors are lectin-like multigenic Ly49 molecules, whereas the single Ly49 gene in humans is nonfunctional. Comparison of KIR receptor evolution in humans and chimpanzees indicates that while NK cells of both species express inhibitory KIR receptors with identical specificity for structural components of HLA-C, the receptors themselves are structurally divergent and not orthologous. The differences between the human and chimpanzee HLA-C-specific KIR are not consistent with neutral evolution and the high sequence similarity in the respective genomes.106

Interactions between trophoblast Class I molecules and other decidual lymphocytes also suggest the importance of Class I molecules in innate immunity at the maternal-fetal interface. Many of the lymphocyte subpopulations that are rare in the peripheral circulation but enriched among decidual lymphocytes are important in innate immunity. These include NKT cells, a newly-described lymphocyte subpopulation with characteristics of both NK cells and T cells.107 In animal models, the presence and quantity of NKT cells at implantation sites is associated with fetally-expressed MHC Class I or Class I like products.108,109 NKT cells and their ligands have been recently demonstrated in human decidual tissues.110

While very few B cells populate the human maternal decidua, T cells are present including those expressing CD8.90,92,111 The presence on these cells of CD8, a classical ligand for MHC Class I interactions, suggests the possibility of a role for trophoblast Class I products in adaptive immunity at the maternal-fetal interface presumably via classical mechanisms. HLA-G has been shown to interact with T cell-expressed CD8 in vitro,112,113 and the peptide-binding cleft of HLA-G can bind a diverse set of antigenic peptides.114 Soluble forms of HLA-G, products of spliced variants of HLA-G mRNA lacking their transmembrane segment,115-117 have been described in amniotic fluid,118 in maternal peripheral blood,119 and in spent embryo culture media.58,59 Soluble classical Class Ia molecules have been shown to promote immune tolerance120,121 and Solier et al.122 have demonstrated that soluble HLA-G molecules specifically promote apoptosis of activated CD8+ T cells, indicating that less traditional interactions of MHC Class Ib molecules may be involved in the trophoblast. Indirect effects of trophoblast Class I products on adaptive immunity may also result from alterations in cytokine secretory profiles by immune cells.93,123 In vitro demonstration that decidual and peripheral immune cells shift toward the Th2 cytokine secretory phenotype when exposed to HLA-G124 supports this hypothesis.

Arguing against an important role for trophoblast MHC Class I products in adaptive immune responses are sentinel characteristics of the molecules themselves. HLA-E and HLA-G have limited polymorphism. This homogeneity is in distinct contrast to classical MHC Class Ia products, whose remarkable level of polymorphism promotes the generation of exquisite immune specificity. The relatively short half-life of HLA-C at the cell surface weakens its prospective importance as an antigen-presenting molecule. The expression of HLA-C in extravillous trophoblast cells, given preferential interactions of HLA-C with NK cell KIR receptors and the preferential homing of NK cells to the endometrium during pregnancy, suggest that this molecule is interacting primarily with components of the older innate immune system rather than the adaptive immune system in the context of early pregnancy.

Conclusions and Future Directions

The paradox of fetal protection from the maternal immune response presents not one but two distinct challenges to our current understanding of transplantation immunobiology. Dissection of the unique coordinate expression and function of HLA-E, HLA-G and HLA-C in selected populations of trophoblast cells appears to be a key prerequisite to understanding the intricate and complex interactions of MHC Class I proteins with components of the innate and adaptive immune systems at the maternal/fetal interface. Coexpression of this unique combination of MHC molecules suggests a critical role for MHC Class I molecules in this most fundamental of biological processes. The apparent absence of any MHC Class I expression in other populations of trophoblast cells in the presence of bountiful NK cell populations presents a second type of fetal/maternal interface that challenges our current understanding of the paradigmatic immune response. Unraveling the control and regulatory mechanisms at work in the trophoblast contains the promise of useful application in inhibition or amelioration of context-specific autoimmune conditions. The spatial and temporal difficulties inherent in studying implantation and placental development in early pregnancy in humans, the unique attributes of human placentation, and the limitations of animal models contribute significantly to the challenges. Development of nonhuman primate models and reagents, an expensive and technically difficult undertaking in its own right, may help to bridge the chasms in our understanding, and progress is being made in this regard.125

All of the problems involved in studying MHC expression and interactions in the trophoblast are equally valid in asking similar questions about the preimplantation embryo, with the added complication of the absence of federal funding for such studies in the United States. Research is underway to dissect the mechanisms of Qa-2 regulation of preimplantation embryonic development in the mouse, which may shed some light on the role of HLA-G in human embryos. HLA-G transgenic mice may be useful in some studies, and efforts to develop resources using nonhuman primates are under way.126 Elucidating the role of MHC in human preimplantation embryos is important for understanding the regulation of very early development in addition to understanding the mechanisms of immunoprotection of the preimplantation embryo.

Given the strong selective pressures operating on both the immune and reproductive systems over time, deciphering the role or roles of MHC Class I genes and proteins during preimplantation development and early pregnancy may also offer glimpses of the mysterious evolution of the MHC. An ancestral role for MHC in “self-aware” mate selection and reproductive behavior predating the development of MHC function in the immune system remains a tantalizing possibility. The importance of the unique MHC Class I interactions with the innate immune system in the trophoblast suggests an ancient and robust association that challenges us to expand the standard model of the role of MHC Class I in defense against pathogens and in surgical transplantation. Rather than trying to accommodate models of MHC Class I interactions in the preimplantation embryo and the trophoblast in the light of lessons learned from surgical transplants, the real challenge is to understand the responses evolved in the context of the only natural vertebrate “transplantation” model, the fetal-maternal interface.


This work was supported by NIH grants HD39215 and HD40309 (to C.M.W.), NSF Engineering Research Center for Subsurface Sensing and Imaging systems (CenSSIS) (EEC-9986821) (to C.M.W.) and NIH grant K12HD00840 (to D.J.S.).

We would like to thank Paula Welter and Sally De Fazio for critical reading of this manuscript.


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