Elsevier

Human Immunology

Volume 61, Issue 11, November 2000, Pages 1086-1094
Human Immunology

Modulation of HLA-G antigens expression in myelomonocytic cells

https://doi.org/10.1016/S0198-8859(00)00191-9Get rights and content

Abstract

As trophoblast cells and macrophages share cellular characteristics, we investigated the expression of HLA-G antigens during the myelomonocytic differentiation. Analyses with the 87G and 16G1 monoclonal antibodies demonstrated that HLA-G was not expressed in peripheral blood monocytes, in in vitro differentiated dendritic cells and macrophages, and in resident mononuclear phagocytes infiltrating healthy tissues. Conversely, activated macrophages and dendritic cells localized in tumoral biopsies of some lung carcinomas expressed HLA-G antigens. Induction of HLA-G expression at the cell surface of the monohistiocytic cell line U 937 with different cytokines strongly suggests that cytokines secreted during inflammation may be involved in this specific upregulation. Bronchoalveolar macrophages collected from patients suffering from acute HCMV pneumonitis also expressed HLA-G molecules. In vitro, we thus demonstrated that HLA-G antigens are produced during viral reactivation in the macrophages generated after allogeneic stimulation of HCMV latently infected monocytes. Our data suggest that inflammatory processes in lung tissues, like tumoral transformation and HCMV acute infection, are likely to induce HLA-G molecules in infiltrating macrophages and dendritic cells. The expression of molecules capable of downregulating both the innate and adoptive immunity could be a mechanism that helps tumoral and HCMV infected cells to escape immune response.

Introduction

The function of the classical MHC-I molecules, HLA-A, -B, -C in immune recognition is well understood both in functional and structural terms. These highly polymorphic molecules constitute transplantation antigens that may be recognized by alloreactive T cells. These molecules also play an important role in the induction of a specific immune response by presenting tumoral or viral peptide antigens to T cells. In contrast, nonclassical MHC-I HLA-G molecules have been described as inhibitors of the cellular immune response. The HLA-G gene is characterized by a limited polymorphism and the alternative transcription of spliced mRNAs that encode at least seven different isoforms, namely the membrane-bound HLA-G1, -G2, -G3, -G4 and soluble HLA-G5, -G6, -G7 proteins [1]. HLA-G antigens are primarily expressed in fetal trophoblast cells that invade the maternal decidua. These invading trophoblast cells fail to express MHC-I HLA-A, -B or MHC-II molecules. Cell surface HLA-G1 and soluble HLA-G5 molecules can bind peptides derived from a variety of intracellular proteins. In vivo, cell surface expression of HLA-G molecules may affect cytotoxicity and antigen presenting functions through binding to LIR-1, LIR-2 and p49 inhibitory receptors 2, 3, 4. Furthermore, soluble HLA-G molecules impair peripheral blood NK lytic activity [5], show strong MLR suppression [6] and trigger CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells [7]. These different in vitro functional studies strongly suggest that cell surface and soluble HLA-G antigens may act as strong immunosuppressive molecules in vivo.

The trophoblast, which forms a physical barrier between the mother and developing fetus, is a component of the host immune system during pregnancy. Of the classical immune cells, it most closely resembles the macrophage, also present in high numbers in the pregnant uterus. The macrophages and trophoblast, as cell classes, share characteristics such as phagocytosis, syncytialization, invasiness, permissiveness to HCMV, expression of the proteins CD4, CD14, IgG receptor (FcR), granulocyte-macrophage–colony stimulating factor (GM-CSF), colony stimulating factor-1 (CSF-1), IL-1, IL-6, tumor necrosis factor (TNF-α), transforming growth factors (TGFs), platelet-αderived growth factor (PDGF), and receptors for theses cytokines. In the uterus, both cell types appear regulated by a common element, the uterine epithelium, that secretes cytokines such as CSF-1, GM-CSF, TNF-α, TGFβ, IL-6, and leukemia inhibitory factor (LIF). These common characteristics and regulation led us to investigate the possible expression of HLA-G antigens in myelomonocytic cells.

Section snippets

Cell lines

Human foreskin fibroblasts (HFF), Jeg3 (choriocarcinoma), U937 (monohistiocytic leukemia), and THP-1 (monocytic leukemia) were obtained from the ATCC. These cell lines were maintained according to the recommendations of the supplier. Culture media (Life Technologies, Inc., Cergy-Pontoise, France) were supplemented with 10% FCS, 1 mM sodium pyruvate, 2 mM glutamine, 10 U/ml penicillin, 100 μg/ml streptomycin, in a humidified 5% CO2 atmosphere. JEG3 choriocarcinoma cell line was used as a

Absence of HLA-G antigen expression in unstimulated myelomonocytic cells

HLA-G antigen expression was searched in monocytes isolated from different normal individuals, in vitro produced dendritic cells and allogeneically differentiated monocyte-derived macrophages at around 10 days of culture. Flow cytometry analyses using the anti-HLA-G mAb, 87G showed that HLA-G antigens were absent at the cell surface of monocytes, dendritic cells, and macrophages. In the same way, no soluble HLA-G antigens were detected by Western blotting and ELISA. Conversely, both cells

Discussion

In this review, we showed that HLA-G translation is tightly regulated in mature myelomonocytic cells under stressful conditions. We never detected HLA-G proteins in peripheral blood monocytes, in cultured uninfected myelomonocytic cells, nor in resident immune cells infiltrating healthy tissues. Conversely, we report the evidence for HLA-G protein expression in tumor infiltrating macrophages and dendritic cells. These HLA-G-positive tumor-infiltrating cells were detected in 5 out 18 different

Acknowledgements

We thank Professors M. P. Ramée and G. Lancien for providing tissue sections; D. E. Geraghty and J. Nelson for their gift of monoclonal antibodies; and Martine Richard for her technical assistance. This work was supported by grants from the Institut National de la Recherche Scientifique et Médicale (CRI 9606) and from the Ministère de la Recherche et de l’Enseignement Supérieur (UPRES-EA 22-33).

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