Antigen presenting cells and HLA-G – a review

doi:10.1016/j.placenta.2005.01.006

Placenta

Volume 26, Supplement, April 2005, Pages S104-S109

https://doi.org/10.1016/j.placenta.2005.01.006 Get rights and content

Maternal antigen presenting cells, which are macrophages and dendritic cells, are scattered throughout human decidualized endometrium during all stages of pregnancy. These powerful, multi-functional leukocytes reside in close proximity to uterine glandular epithelium, uterine blood vessels, and HLA-G-producing invasive cytotrophoblast cells. Macrophages and dendritic cells, which express the HLA-G receptors, ILT2 and ILT4, play major roles in driving innate and adaptive immune responses, altering the behavior of local stromal cells, shaping the cytokine microenvironment, and protecting the tissue from infection. Therefore, encounters between decidual antigen presenting cells and HLA-G molecules are likely to influence uterine and placental homeostasis as well as local maternal immune responses to the fetus during pregnancy.

Section snippets

Macrophage origin and function

Human monocytes and macrophages are mononuclear phagocytic cells that comprise a major arm of both the innate and adaptive immune system. In adults, pluripotent myeloid stem cells in the bone marrow differentiate into several types of progenitor cells, including granulocyte–monocyte progenitors. These progenitors differentiate into promonocytes, which depart the bone marrow and enter the blood stream. After circulating for approximately 8 h, promonocytes differentiate into mature monocytes,

Dendritic cell origin and function

Dendritic cells, which are closely related to macrophages, are considerably more potent antigen presenters than macrophages. Human dendritic cells include those of lymphoid origin (plasmacytoid), non-hematopoietic origin (follicular cells of the lymph nodes), and myeloid origin (myeloid). Several reviews describe these dendritic cell sub-populations and their origins [12], [13]. In this commentary we focus on the myeloid dendritic cell population, as this is the type found in the human uterus.

Phenotypes of decidual APC

Several populations of HLA class II⁺ APC have been described in decidualized human endometrium (Figure 1), including activated macrophages comprising approximately 20% of decidual leukocytes [17], [18], mature (CD83⁺) dendritic cells comprising approximately 1% of decidual leukocytes [19], [20], [21], and a more recently described population of immature (CD83⁻) macrophage/dendritic cell-like cells [20], [22]. This immature cell type appears to be composed of multiple, related cell types, some

HLA-G and the ILT receptors

The question then arises as to how decidual APC are driven into immune inhibitory profiles. Placental HLA-G, a product of infiltrating fetal cytotrophoblast cells, is a reasonable possibility. The HLA-G gene has unique features, including generation of multiple isoforms by alternative splicing of a single message giving rise to four membrane-bound isoforms (HLA-G1 through -4) and three soluble isoforms (HLA-G5, -G6, and -G7), generated by the inclusion of intron 4, which encodes a premature

APC: targets for HLA-G-induced immune-suppression?

Several studies have indicated that HLA-G may suppress APC functions, but reports published to date fail to show that HLA-G is acting specifically at the level of the APC. For example, HLA-G-transgenic mice, which express HLA-G ubiquitously, have decreased skin allograft rejection and increased circulating immature myeloid cells [45]. Injection of HLA-G tetramers into mice results in detectable tetramer binding only to dendritic cells and decreased graft rejection [45], [46]. In both of these

Does HLA-G induce apoptosis in APC?

Because two groups have reported that soluble HLA-G1 induces apoptosis in CD8⁺ lymphocytes [48], [49], [50], investigators have studied the viability of APC exposed to HLA-G. The results to date are negative. HLA-G does not decrease the viability of immature or mature monocyte-derived dendritic cells, does not alter differentiation of dendritic cells from blood monocytes, and does not affect maturation of dendritic cells [47]. In agreement with this study, we observed no loss of viability in

Does HLA-G induce immune-suppressive cytokines?

Because decidual macrophages are known to produce IL-10 and TGF-β1, we tested the production of these cytokines by PMA-differentiated, interferon (IFN)γ-activated U937 cells [51], IFNγ-activated peripheral blood monocytes, and IFNγ-activated monocyte-derived macrophages treated with the recombinant HLA-G5 and -G6 proteins. In the U937 model, low doses of HLA-G5, similar to concentrations of soluble HLA-G reported in circulating blood, slightly induced IL-10 secretion. By contrast, high doses of

Do APC express HLA-G?

Given the reported effects of HLA-G on lymphocyte responses, the question of APC expression of HLA-G as a method of immune-modulation has recently been addressed experimentally. LeMaoult et al. [53] showed that HLA-G1-transfected myelomonocytic cell lines (KG1a and U937) suppressed CD4⁺ T cell proliferation in a mixed lymphocyte reaction, and the resultant T cells had an immune-suppressive phenotype. This study raises the question of whether naturally occurring APC express HLA-G in vivo.

Despite

Future directions

Given the critical role of innate immune cells in host protection against infection as well as the development of adaptive immune responses, further studies on the effects of HLA-G on APC are needed. Future studies are expected to focus on functionally and phenotypically distinct APC populations and their multitude of activities, which include migration, cytokine production, phagocytosis, antigen processing, and antigen presentation. With regard to studies of HLA-G influencing the actions of

Acknowledgements

This work was supported by grants from the National Institutes of Health to JSH (P20 HD39878), a fellowship from the KUMC Biomedical Training Program to RHM, and the U54 Reproductive Sciences Center (HD33994).

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The human leukocyte antigen (HLA) G was heavily expressed by the human placenta; it was also expressed in two main isoforms (membrane bound and soluble [17]). The HLAG can interact with inhibitory receptors of natural killer (NK) cells, e.g., immunoglobulin-like transcript (ILT) -2 and -4 [18]; these receptors were also present on other immune cells (i.e., macrophages and dendritic cells [19]). Furthermore, HLAG was detected systemically in pregnant women [20] and probably had a role in pregnancy-related immune changes in human.
Eutherian mammals share a common ancestor that evolved into two main placental types, i.e., hemotrophic (e.g., human and mouse) and histiotrophic (e.g., farm animals), which differ in invasiveness. Pregnancies initiated with assisted reproductive techniques (ART) in farm animals are at increased risk of failure; these losses were associated with placental defects, perhaps due to altered gene expression. Developmentally regulated genes in the placenta seem highly phylogenetically conserved, whereas those expressed later in pregnancy are more species-specific. To elucidate differences between hemotrophic and epitheliochorial placentae, gene expression data were compiled from microarray studies of bovine placental tissues at various stages of pregnancy. Moreover, an in silico subtractive library was constructed based on homology of bovine genes to the database of zebrafish — a nonplacental vertebrate. In addition, the list of placental preferentially expressed genes for the human and mouse were collected using bioinformatics tools (Tissue-specific Gene Expression and Regulation [TiGER] — for humans, and tissue-specific genes database (TiSGeD) — for mice and humans). Humans, mice, and cattle shared 93 genes expressed in their placentae. Most of these were related to immune function (based on analysis of gene ontology). Cattle and women shared expression of 23 genes, mostly related to hormonal activity, whereas mice and women shared 16 genes (primarily sexual differentiation and glycoprotein biology). Because the number of genes expressed by the placentae of both cattle and mice were similar (based on cluster analysis), we concluded that both cattle and mice were suitable models to study the biology of the human placenta.
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Citation Excerpt :
This may suggest that fusion of trophoblast cells into MTGC plays a role in preventing trophoblastic cells from invading into the deeper layers of the uterine wall, and thereby may be crucial for the normal detachment of the placenta after birth. The aim of the study was to explore any differences in the presence and proliferation of EVT [21,22], HLA-G expression by EVT [8,21,23,24], and/or the presence of immune competent cells [13,15,25] in the basal decidua between placenta adhesiva and control placentas. The study design was that of a descriptive analysis of immunohistochemical differences in the basal decidua of 17 PA and 10 CP, all from healthy term patients.
Retained placenta is caused by abnormal adherence of the placenta to the uterine wall, leading to delayed expulsion of the placenta and causing postpartum haemorrhage. The mildest form of retained placenta is the placenta adhesiva (PA), of which the cause is unknown.
The aim of our study was to explore possible differences in immune response in the basal decidua between PA and control placentas (CP). We performed a descriptive analysis of immunohistochemical differences in 17 PA and 10 CP.
Our results show that in PA the amount of uterine natural killer (uNK) cells is significantly reduced (0.2 uNK cell/standardised area) as compared to CP (9.8 uNK cell/standardised area, p < 0.001) whereas the number of trophoblast cells and the expression of HLA-G by trophoblast are similar in the decidua of PA and CP.
We speculate that adequate numbers of uNK cells in the basal decidua are needed for normal expulsion of the placenta.

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Antigen presenting cells and HLA-G – a review

Section snippets

Macrophage origin and function

Dendritic cell origin and function

Phenotypes of decidual APC

HLA-G and the ILT receptors

APC: targets for HLA-G-induced immune-suppression?

Does HLA-G induce apoptosis in APC?

Does HLA-G induce immune-suppressive cytokines?

Do APC express HLA-G?

Future directions

Acknowledgements

Immunol Today

Res Immunol

J Reprod Immunol

J Immunol Methods

Am J Pathol

Am J Pathol

Immunobiology

J Reprod Immunol

Cell Immunol

Immunity

J Reprod Immunol

Hum Immunol

Hum Immunol

Hum Immunol

Hum Immunol

Am J Pathol

Functional plasticity of macrophages: reversible adaptation to changing microenvironments

J Leukoc Biol

The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum

Am J Pathol

Wound repair: overview and general considerations

Potential role of macrophages as immunoregulators of pregnancy

Reprod Biol Endocrinol

The instructive role of innate immunity in the acquired immune response

Science

The many faces of macrophage activation

J Leukoc Biol

The inflammatory macrophage: a story of Jekyll and Hyde

Clin Sci (Lond)

Alternative activation of macrophages

Nat Rev Immunol

Dendritic cells and the control of immunity

Nature

Tolerogenic dendritic cells

Annu Rev Immunol

Dendritic cells as the terminal stage of monocyte differentiation

J Immunol

Myeloid dendritic cells

J Leukoc Biol

Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction

Immunol Rev

Cell populations in human early pregnancy decidua: characterization and isolation of large granular lymphocytes by flow cytometry

Immunology

Dendritic cells in the human decidua

Biol Reprod

Predominance of Th2-promoting dendritic cells in early human pregnancy decidua

J Leukoc Biol