HLA and maternal-fetal recognition.

HLA and mat4’nal-fetal

recognition

S. HUN’141 AND HARRY T ORRt *Deprtuient of’athology antf Oncology, University

JOAN

of Laboratory

USA, and tDepatment

Minnesota,

Min4eapohs,

Minnesota

Despite genetic differences, mothers do not reject their semiallogeneic embryos. Regulated expression of the major histocompatibility antigens (lILA) by placental trophoblast cells, which intervene between the embryo and maternal blood and tissues, is now believed to play an important role in this surprising feature of pregnancy. Transcription and translation of the highly polymorphic class I HIA-A, -B, -C genes whose products stimulate graft rejection are blocked in trophoblast cells. Instead, these cells express HLA-G, a nonpolymorphic gene. Moreover, the cells do not express class II HIA-D antigens, and factors such as interferons that usually enhance HLA expression have no effect on trophoblast cells in situ. Thus, multiple regulatory mechanisms prevent the cells that sequester the embryo from the mother from expressing the potentially deleterious paternal HLA antigens, immunological rejection is avoided and successful pregnancy ensues.Hunt, J. S.; Orr, H. T. HLA and maternal-fetal recognition. FASEBJ. 6: 2344-2348; 1992. antigens’

genes

HLA

.

placenta’

trophoblast

ARE INTERNALIZED IN humans and other mammals, a biological adaptation that provides protection from environmental hazards. Such an arrangement poses a new problem; the intimate juxtaposition of maternal and fetal cells should allow ample opportunity for the development of maternal immune responses to paternally derived antigens. Yet, unexpectedly, there is no evidence for graft rejection and pregnancy proceeds unimpeded. Many hypotheses have been advanced to explain the unique immunological status of the fetal semiallograft. Chief among those are 1) immunosuppressive environmental conditions (1), 2) expression of regulatory proteins that interfere with the complement cascade (2), and 3) the provision of an immunologically inert barrier between maternal and fetal cells (3). Although strong evidence has accumulated for all three, in this review we focus on trophoblast cells in the placenta, a specialized population of cells that intervenes between the mother and the embryo. These strategically positioned cells regulate expression of their class I HLA genes in a uni-

EMBRS

que fashion. Because the products of these central to immune recognition and subsequent

genes are rejection

of grafts, their pattern of expression by trophoblasts likely to have a critical role in maternal-fetal recognition. Class II HLA antigens, which might also participate graft rejection, are unexpressed in trophoblast cells.

2344

THE

Center,

Medical

Medicine and Pathplogy 55458, USA

ABSTRACT

Key Words:

f

and Institute

TROPHOBLAST

Kan*s

of Human

City,.

*

66103,

Genetics,

BARRIER

Cells derived from the inner cell mass of the blastocyst gradually develop both class I and class II HLA during the course of gestation (4, 5), thereby acquiring the capacity to stimulate and serve as targets for maternal anti-fetal cytotoxic cells and antibodies. Maternal antibodies to paternally derived fetal HLA are common in the sera of multiparous women (6), although it has been difficult to demonstrate cytotoxic T lymphocytes specific for paternal HLA. The HLA-expressing embryonic cells of inner cell mass origin are completely encased in a protective shell composed of trophoblast cells in the placenta and extraplacental membranes, which arise from the trophectoderm layer of the blastocyst. Trophoblast cells have many functions, including transportation of nutrients from the mother to the fetus and synthesis of various hormones and growth factors. Several subpopulations of trophoblast cells can be

identified

by anatomic

location,

morphology,

and

state

of differentiation (Fig. 1). In the placenta, fully differentiated syncytiotrophoblast forms a continuous cell layer that is exposed to maternal blood. Villous cytotrophoblastic cells, which are abundant in early placentas but uncommon in term tissues, are located directly beneath the syncytium. In the early stages of pregnancy, cytotrophoblastic cells proliferate rapidly and migrate

from the placental villi into the uterus, anchoring the placenta and allowing expanded blood flow by replacing the endothelial progresses, the and extravillous membrane.

cells of the spiral arteries. As gestation cytotrophoblastic cells are less invasive, cells regress to form the chorionic

CHARACTERISTICS ANTIGENS HLA class I antigens netic loci, each with lation. The major containing the HLA of chromosome 6 at

OF THE

HLA

GENES

AND

are the products of multiple gea large pool of alleles in the popuhistocompatibility complex (MHC)2 genes is found within the short arm t3p2l.l to 6p21.3. Class I genes are

‘To whom correspondence should be addressed; at: Department of Pathology and Oncology, University of Kansas Medical Center, 39th Street and Rainbow Blvd., Kansas City, KS 66103,

is

USA.

in

2Abbreviations: MHC, major histocompatibility TcR, T cell receptor; 2m, 132-microglobulin; IFN, HLA, histocompatibility antigens.

1

0892-6638/92/0006-2344/$0l

complex; interferon;

.50. © FASEB

www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on November 19, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber

1st Trimester

Term Chorion

Membrane

ever, the level of expression varies considerably among cells and tissues. Although class I gene expression, which requires the production of a functional molecule on the cell surface, depends on many steps of RNA and protein processing, a central point of regulation is that of RNA transcription. The regulation of MHC class I gene transcription by RNA polymerase H is a complex process involving specific class I gene DNA sequence elements and trans.acting protein factors. Deletion analysis of DNA flanking the 5’ end of class I genes and expression studies in transfected cells have shown that at least two DNA regions, enhancer A (-190 to -160 relative to the cap site) and enhancer B (-120 to -61), are important in transcription (19-22). In addition, an interferon

(IFN) consensus sequence has been located -137 (23) that facilitates the ability of IFN Placenta

Placenta

Figure 1. A schematic representation of the trophoblastic cell subpopulations in first trimester and term tissues. Stippling identifies the trophoblast cells that contain the W6/32-binding protein, HLA-G. cTB, cytotrophoblastic cells; sTB, syncytiotrophoblast. located at the distal end of this region, spanning almost 2000 kb of DNA. Southern blot, cloning, and sequence analysis have revealed 17 class I genes or gene fragments (7). Besides the three classical genes HLA-A, -B, and -C that encode the major transplantation antigens, the class I gene family includes three other genes designated HLA-E, -F, and -G (8-12). The remaining class I DNA sequences are pseudogenes and partial gene fragments. MHC class I molecules present antigens to the T cell receptor (TcR) on CD8 positive T lymphocytes, primarily cytotoxic T cells. The recent elucidation of the crystal structure of an HLA-A class I antigen has provided many insights into the molecular basis by which class I antigens bind antigenic peptides and transport them to the cell surface for presentation to T cells (13). Class I antigens, HLA-A, -B, and -C, were initially characterized as a result of their role in allogeneic tissue graft rejection, and thus their designation as the major transplantation antigens. This latter point has important implications in terms of HLA-A, -B, and -C expression by fetal tissues during gestation as described below. Other functions of these antigens include interactions with receptors for insulin and epidermal growth factor (14, 15). The nonclassical HLA class I genes, HLA-E, -F, and -G, are notably nonpolymorphic and their functions remain unknown. Transfection experiments into a mutant, class I-null B-lymphoblastoid cell line demonstrated that the products of all three genes could associate with microglobulin (m, the HLA light chain) but that only the HLA-G antigen was expressed on the cell surface (16). The proteins were identified by using the monoclonal antibody W6/32, which binds to a combinatorial determinant on associated heavy and light chains (17). Subsequent experiments showed that HLA-E and HLA-F mRNA were contained in a variety of tissue and cell types whereas HLA-G transcripts were limited to extraembryonic tissues (18). The lack of polymorphism and the highly defined locale of expression suggest that any antigen presentation function of HLA-G is very limited and specific. In contrast to HLA-G, classical HLA class I genes are constitutively expressed on nearly all somatic cells. How-

HLA IN TROPHOBLAST

CELLS

at -165 to to increase

class I transcription (24). Of particular relevance to studies of extraembryonic tissues, the 5’ flanking region of HLA-G has a 13-bp deletion that is located within the enhancer A/IFN consensus sequence region (10, 11).

HLA

GENE

EXPRESSION

IN TROPHOBLAST

CELLS

Medawar (25) first suggested that protection of the embryo from immunological rejection could be accomplished if placental cells failed to express foreign antigens. Supporting experimental evidence was provided in 1976 by Faulk and Temple (26) and Goodfellow and co-workers (27), who demonstrated that the syncytiotrophoblast in term placentas did not bind maternal antibodies to paternal HIA. Later, in situ hybridization experiments showed that term syncytiotrophoblast lacked class I HIA mRNA (28), which provided an explanation for the paucity of these antigens. Figure 2 shows that HLA class I mRNA-positive mesenchymal cells in term placental villi are sequestered beneath an HLA class I mRNA negative layer of syncytiotrophoblast. The notion that trophoblast HLA negativity accounted for immunological protection of fetal cells was seriously challenged in 1981, when Sunderland and co-workers (29) reported that extravillous cytotrophoblastic cells in first trimester placentas were class I HLA positive (Fig. 1). Subsequent experiments showed that this was also true of cytotrophoblastic cells in the chorion membrane (30). However, the antigens were unusual in that they bound W6/32 and antibodies to 2m but not other monoclonal antibodies to class I HLA (30), and were lower in mol. wt. (-40,000) than expected (-45,000) (31). Possible explanations for these unexpected findings were that 1) cross-reactive epitopes rather than class I HLA were detected by the monoclonal antibodies, and 2) the immunohistochemical observations were correct but trophoblast cells transcribed a nonclassical class I gene whose products were identified by some but not all antiHLA reagents. We used in situ hybridization to show that cytotrophoblastic cells did indeed contain class I HLA mRNA (28, 32), thus eliminating the first possibility. It remained, then, to learn which among the various members of the class I gene family was transcribed and translated in cytotrophoblastic cells.

DISCOVERY

OF HLA-C

Experiments

by Ellis

evidence

cells

that

were

the

transcribed

class

IN TROPHOBLAST and

co-workers

I gene

from

CELLS

supplied the first in trophoblastic nonclassical gene, HLA-

products

the

2345


I

to term,

and

Final tic

indicated

that

transcription of this gene was tissues (18). transcription in cytotrophoblas-

to extraembryonic

restricted

proof

cells

of HLA-G

was

ments

(Fig.

probes

(K.

provided

2).

by

Both

K.

450

Yelavarthi

in

bp and

situ

hybridization

(36)

J.

S.

and Hunt,

experi-

oligonucleotide unpublished

results) specific for HLA-G tic cells in first trimester

hybridized tissues and

brane

cells in first trimester

cells.

Mesenchymal

to cytotrophoblasto chorion mem-

but not

term placental villi contained HLA-G mRNA. This finding indicates that gene switching within the multigene class I family occurs in the placental mesenchymal cells, a postulate that is supported by observations on eye and thymus tissues (37).

REGUlATION

GENE

OF

TROPHOBLAST

CELL

CLASS

I

EXPRESSION

Three types of regulation appear to control trophoblast cell class I HLA expression. First, transcription of all of the class I heavy-chain genes is prevented in syncytiotrophoblast. Second, controls on translation appear to operate in human villous cytotrophoblastic cells, which in first trimester placentas contain HLA-G mRNA (36) but do not express detectable levels of the protein (38). Third, cytotrophoblastic cells external to the villi select a specific member of the class I gene family, HLA-G, for

transcription

Figure

of HLA class I gene RNA in term and A) A class I heavy-chain antisense RNA probe (pHLA1A) hybridizes to RNA in placental villous mesenchymal cells whereas no hybridization is seen in the synycytiotrophoblast layer (arrows). B) A 450-bp antisense RNA probe specific for HLA-G hybridizes to cytotrophoblastic cells in a placental villus (small arrow) and to cytotrophoblastic cells emerging from the villus into a maternal blood space (large arrows) as well as to villous mesenchymal cells (arrowhead). In both experiments, the HLA probes were biotinylated, and hybridization was detected with a streptavidinalkaline phosphatase conjugate (28, 32, 36). Original magnification, x 313. first

2. Expression

trimester

placentas.

C. Trophoblast-derived choriocarcinorna cells, the Jar and BeWo cell lines, have been used extensively to examine class I HLA in trophoblast cells. A cDNA library from BeWo cells yielded an HLA-C-like sequence (33) as well as a second smaller clone, which in subsequent experiments was shown to have sequence homology with HIA-G (34). The same sequences were demonstrated by polymerase chain reaction in cells obtained from term chorionic membranes. Thereafter, freshly harvested cells from first trimester placentas were shown to contain W6/32-precipitated proteins that comigrated on two-dimensional gels with W6/32-precipitated proteins from HLA-G transfected cells (35). Also, RNA sequences that hybridized to an HLA-G probe were present, and levels of transcripts were higher in first trimester placentas, where cytotrophoblastic cells are abundant, than in term placentas. Gene-specific RNase protection assays showed decreasing levels of HLA-G in the placenta as gestation progressed

and

translation.

A closed chromatin configuration, which is associated with hypermethylation of DNA and inhibition of ti-anscription, may account for the lack of class I HLA in syncytiotrophoblast. Jar cells, which do not transcribe the heavy-chain genes but contain ample 2m, synthesize class I heavy chains after treatment with demethylating agents (39, 40). Alternatively or additionally, a negative regulatory element may prohibit HLA class I transcription in trophoblast as it does in embryonal carcinoma cells (41). A regulatory mechanism operating at the level of translation may be unique to trophoblast cells. Although there are many examples of this type of control in other systems, none of these have yet been demonstrated for class I HLA. Gene selection in multigene families is under intensive investigation. Both cis and trans-acting elements have been identified in the albumin (42) and globin (43) families. These two families, as with class I HLA, contain genes that are specifically selected for expression during embryogenesis. The degree to which trophoblast cell HLA class I genes respond to known inducing factors is as yet unclear. Syncytial and cytorophoblast cells in first trimester and term placental villi contain immunoreactive IFN (44) as well as another class I HLA-enhancing factor, tumor necrosis factor-a (45), yet remain class I HLA negative. Moreover, experiments in which explants of first trimester tissues were treated with IFN failed to demonstrate any increase in class I antigen expression by trophoblast cells (38). These results suggest that the deletion noted in the 5’ DNA sequences of the HLA-G gene might confer unresponsiveness to endogenous modulators. In contrast to cells in situ, cytotrophoblastic cells isolated from placentas and cultured in vitro have been shown to contain IFN-inducible class I mRNA (46). Determining whether these messages were transcribed from HLA-G or other class I genes is exceedingly difficult because of minor contamination with HLA-A, -B, -C-expressing cells. However, the observa-

The FASEB Journal HUNT AND ORR 2346 Vol. 6 March 1992 www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on November 19, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber

dons raise the intriguing possibility that tissue-specific mechanisms might contribute in some way to trophoblast cell regulation of class I HLA expression.

ANIMAL

MODELS

Comparisons among species with similar placentation indicate that controls on transcription, translation, and gene selection are not limited to trophoblast cells in human placentas. There are striking similarities in the placentas of both mice and rats. Mouse placental class I heavy chain message is contained in giant trophoblast cells and large trophoblasts in the spongy region of the placenta that is located near maternal tisue whereas little heavy chain mRNA is found in labyrinthine trophoblast, the placental region that is closest to the embryo (47). Patterns of antigen expression are the same as for message with the exception of giant cells, which do not express immunohistochemically detectable class I antigens (48). A lack of 132 m in these latter cells might account for the absence of antigens (49). As with human trophoblast, IFN effects differ among mouse subpopulations; although in vivo administration of IFN during late stages of pregnancy enhances class I antigen expression in large spongy region trophoblasts, it has no effect on giant cells or labyrinthine trophoblast (48). Experiments on HLA-B transgenic mice showing no transcription of the gene in trophoblast cells (50) indicate that different mechanisms control placental expression of endogenous

class I genes

and

this particular

human

AND

PERSPECTWES

Regulated expression of HLA in trophoblast cells forming the interface between the mother and the embryo could account in large part for the surprising willingness of mothers to accept foreign tissue. Regulation is accomplished by controls on transcription and translation,

HLA IN TROPHOBLAST

CELLS

REFERENCES 1.

Beer,

A. E., and

uterine, 2.

transgene.

Although nonclassical class I MHC transcripts have not been identified in mouse placentas, rat trophoblast cells select a nonclassical class I gene, Pa, for expression (51). Unlike human trophoblast cells, the rat trophoblast cells also contain classical antigens. Although these bear paternally derived epitopes, they do not seem to be expressed on trophoblast cell surfaces during allogeneic pregnancy. Maternally derived class I antigens are not detectable in the trophoblast cells, which is in accordance with experiments showing that paternal genes are preferentially expressed in extraembryonic tissues as a consequence of early imprinting events (51, 52). Because of the similarities between human and rodent placental expression of the class I genes, HLA-G transgenic mice would be helpful in defining regulatory mechanisms that control class I MHC gene expression in the placenta. Preliminary results in our laboratory (H. T. Orr, unpublished results) indicate that establishment of such lines is entirely feasible. Structurefunction relationships for this unconventional antigen may also be resolved by using the transgenic mice and cell lines derived from their tissues. With regard to this latter point, mice deficient in 132m and, consequently, in all of the class I antigens, develop normally (53). Thus, other types of molecules are probably capable of substituting for class I antigens when necessary.

CONCLUSIONS

by selection of the nonpolymorphic gene, HLA-G, in preference to the highly polymorphic FILA-A, -B, -C antigens, and by resistance to the enhancing effects of growth factors. Taken together, these data supply strong support for the postulate that trophoblast cells are designed by nature to form an immunologically inert barrier between the mother and the fetus. However, performance of the definitive experiments that would link enhanced expression to rejection has eluded experimentalists thus far because of the many mechanisms preventing up-regulation. Transgenic mice and transfected cells comprise powerful model systems for investigating regulatory events and for exploring functional aspects of HLA-G, which seems to be the only class I HLA gene transcribed by trophoblast cells in situ. These experiments, first designed for learning more about the natural circumstance of pregnancy, may provide some general insights on the mechanisms that allow host accommodation of foreign or altered tissues. As with trophoblast cells, tumor cells often have low levels of class I HLA, and in some instances lack a full complement of the antigens (54).

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Vol. 6

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f1-micoglobulin transcripts at Immunol. 147, 2740-2749 Mattsson, R., Holmdahl, R., Scheynius, A., Bernadotte, F., Mattsson, A., and Van der Meide, P. H. (1991) Placental MHC class I antigen expression is induced in mice following in vivo treatment with recombinant interferon-gamma.]. Reprod. ImmunoL 19, 115129 Jaffe, L., Jeannotte, L. Bikoff, E. K, and Robertson, E. J. (1990) Analysis of 3s-microgloblin expression in the developing mouse embryo and placenta.]. Immunol. 145, 3474-3482 Oudejans, C. B. M., Krimpenfort, P., Ploegh, H. L., and Meijer C. J. L. M. (1989) Lack of expression of HLA-B27 gene in transgenic mouse trophoblast.]. Exp. Med. 169, 447-456 Kanbour-Shakir, A., Zhang, X., Rouleau, A., Armstrong, D. T., Kunz, H. W, MacPherson, T. A., and Gill, T. J., III (1990) Gene imprinting and major histocompatibility complex class I antigen expression in the rat placenta. Proc.Nail. Acad. Sci.USA 87, 444448 Surani, M. A. H. (1986) Evidences and consequences of differences between maternal and paternal genomes during embryogenesis in the mouse. In Experimental Approaches to Mammalian Embiyonic Development (Rossant, J., and Pederson, R. A., eds) pp. 401-435, Cambridge Univ. Press, Cambridge, U.K Koller, B. H., Marrack, P., Kappler,J. W., and Smithies, 0. (1990) Normal development of mice deflicient in beta 2m, MHC class I proteins, and CD8+ T cells. Science248, 1227-1230 Momberg, F., Ziegler, A. Harpprecht, J. Moller, P., Moldenhauer, C., and Hammerling, G.J. (1988) Selective loss of HIA-A or HLAB antigen expression in colon carcinoma. j ImmunoL 142, 352-358

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1992

The FASEB Journal

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On the relative immunogenicity of DR alloantigens: T cell recognition of HLA-DR2a and HLA-DR2b.

Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1.

HLA restriction of human cytotoxic T lymphocytes specific for influenza virus. Poor recognition of virus associated with HLA A2.

Cytotoxic T cell recognition of an endogenous class I HLA peptide presented by a class II HLA molecule.

T cell recognition of self-human histocompatibility leukocyte antigens (HLA)-DR peptides in context of syngeneic HLA-DR molecules.

Structural requirements for recognition of the HLA-Dw14 class II epitope: a key HLA determinant associated with rheumatoid arthritis.

Positive correlation between oligonucleotide typing and T-cell recognition of HLA-DP molecules.

Different recognition of transgenic HLA-DQw6 molecules by mouse CD4+ and CD8+ T cells.

Polymorphic DQ alpha and DQ beta interactions dictate HLA class II determinants of allo-recognition.

Erratum for O'Connor et al., Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1.

Uptake of CCR7 by KIR2DS4⁺ NK cells is induced upon recognition of certain HLA-C alleles.

Cytomegalovirus-Infected Cells Resist T Cell Mediated Killing in an HLA-Recognition Independent Manner.

Structural model for T-cell recognition of HLA class II-associated alloepitopes.

delta T cell clone.

Immune recognition of HLA molecules downmodulates CD8 expression on cytotoxic T lymphocytes.

Elevation of c-MYC disrupts HLA class II-mediated immune recognition of human B cell tumors.

T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease.

Cross-recognition of a mouse H-2-peptide complex by human HLA-restricted cytotoxic T cells.

Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition.

KIR3DS1-Mediated Recognition of HLA-*B51: Modulation of KIR3DS1 Responsiveness by Self HLA-B Allotypes and Effect on NK Cell Licensing.

Differences in specificity of "DPw2-specific" cytotoxic T cell clones revealed with HLA-mutant lines: evidence that non-DP HLA genes influence recognition by some clones.

Adenovirus expressing β2-microglobulin recovers HLA class I expression and antitumor immunity by increasing T-cell recognition.

Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice.

Specificity, degeneracy, and molecular mimicry in antigen recognition by HLA-Class II restricted T cell receptors: implications for clinical medicine.