Modulation of HLA-G antigens expression in myelomonocytic cells
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.
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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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2007, Seminars in Cancer BiologyCitation Excerpt :The demonstration of HLA-G expression in tumor lesions strongly suggests that this expression is under the control of environmental factors, such as virus, cytokines, hormones, stress factors, nutrient deprivation, and increased acidity. In this regard, we and others have previously described that stress proteins [31] as well as cytokines such as GM-CSF [32], IFNs [33–36], IL-10 [37] and LIF [38] up-regulate HLA-G protein expression in tumor cells. Nevertheless, cytokines have no effect on the induction of HLA-G gene transcription in tumor cells in which the HLA-G gene is repressed.
Clinical and biological significance of HLA-G expression in ovarian cancer
2007, Seminars in Cancer BiologyCitation Excerpt :Interaction between cytokines and tumor cells regulates HLA-G expression. For example, GM-CSF and IFN-γ secreted by the infiltrating cytotoxic T cells have been shown to enhance HLA-G expression in tumor cells [17,43,44]. On the other hand, secretion of IL-10 by tumor cells can also upregulate HLA-G expression level in tumor tissues through an autocrine or paracrine fashion [18,33,34].
Report of the Wet Workshop for quantification of soluble HLA-G in Essen, 2004
2005, Human ImmunologyAntigen presenting cells and HLA-G - A review
2005, PlacentaCitation Excerpt :The discrepancies in these studies suggest variation between individual subjects as well as the reactivity of the antibodies used for detection. HLA-G expression by APCs in vivo is more clearly established in pathologic conditions such as CMV infection [58], lung carcinoma [59,60], non-tumoral pulmonary disease [60], HIV infection [61], psoriasis of the skin [62], and breast cancer [63]. In these states of chronic inflammation or cancer progression, the expression of HLA-G by APC might be detrimental to the host, as this would potentially suppress other APC in the pathologic tissue as well as lymphocytes that are needed for control of infection or malignancy.