Mol. Hum. Reprod. Advance Access originally published online on January 29, 2004
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Molecular Human Reproduction, Vol. 10, No. 3, pp. 189-195, 2004
© European Society of Human Reproduction and Embryology 2004
Membrane-bound HLA-G activates proliferation and interferon-
production by uterine natural killer cells
1Department of Blood Transfusion and Transplantation Immunology, 2Department of Gynaecology and Obstetrics, University Medical Centre Nijmegen, Nijmegen and 3Department of Pharmacology, NV Organon, 5342 CC Oss, The Netherlands
4 To whom correspondence should be addressed at: Department of Blood Transfusion and Transplantation Immunology (603), University Medical Centre Nijmegen, P.O.Box 9101, Nijmegen, The Netherlands. e-mail: A.vandermeer{at}abti.umcn.nl
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ABSTRACT |
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The expression of HLA-G by invading trophoblasts suggests a role for this molecule in embryo implantation. Putative targets for HLA-G are the uterine natural killer cells (uNK) that are abundantly present at the time of implantation. Since NK cells are potent producers of a variety of cytokines, interaction with HLA-G may result in the production of cytokines involved in trophoblast differentiation or tissue remodelling. In the present study we investigated the effect of membrane-bound HLA-G (mHLA-G) on the uterine mononuclear cell population (UMC) as a whole and on uNK cells in particular by measuring proliferation and cytokine production [interferon-
(IFN-)/vascular endothelial growth factor (VEGF)/leukaemia inhibitory factor (LIF)/interleukin-3 (IL-3)]. Uterine cells were isolated from endometrium of non-pregnant women at the time that the endometrium is thought to be receptive to implantation, and then co-cultured with HLA-class I–/HLA-class II+ 721.221 B-LCL cells transfected with mHLA-G. HLA-G suppressed the alloproliferative response of unfractionated UMC to 721.221 cells. Also, IFN- and IL-3 production was strongly reduced. In contrast, purified uNK cells were stimulated by mHLA-G. Proliferation as well as IFN- production was increased after co-culture with mHLA-G transfected 721.221 cells. HLA-G stimulated VEGF production by UMC as well as purified uNK cells. LIF-levels were below the detection level of our enzyme-linked immunosorbent assay. In conclusion, our data show that mHLA-G stimulates proliferation and cytokine production by NK cells, while down-modulating the response of unfractionated UMC. Key words: Key words: 721.221 cells/cytokine/endometrium/HLA-G/NK cell
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Introduction |
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Implantation of the embryo in the uterus is a critical event in human pregnancy. During this event, fetal trophoblast cells attach to and invade the maternal decidua, altering the tissue in such a way that an appropriate blood flow to the placenta can develop. A typical characteristic of the invading trophoblasts is the expression of the non-classical MHC molecule HLA-G, besides HLA-C and HLA-E (King et al., 1996, 2000).
HLA-G, in contrast to the classical HLA class I molecules, has a restricted tissue distribution and low polymorphism. Expression is limited to thymic epithelial cells and to the fetal–maternal interface, where it is expressed by invasive trophoblast cells. Also, it is found to be present in amniotic fluid. Recent data suggest that HLA-G expression is also induced in peripheral organs/tissues under certain pathological conditions (Lila et al., 2000; Aractingi et al., 2001). Seven splice variants of HLA-G exist, four membrane-bound forms and three soluble forms. Although there still is debate on the expression and function of the different isoforms, it is well established that the full-length membrane-bound and soluble forms, HLA-G1 and G5 respectively, are expressed, stable and functionally active (Bainbridge et al., 2000b; Mallet et al., 2000; Riteau et al., 2001). So far, three different receptors have been identified that can putatively interact with HLA-G, i.e. ILT2 (Colonna et al., 1997; Allan et al., 1999), ILT4 (Allan et al., 1999) and KIR2DL4 (Ponte et al., 1999; Rajagopalan and Long, 1999). These receptors are present on the different leukocyte populations that are present in the endometrium, i.e. natural killer (NK) cells (KIR2DL4 and ILT2), subsets of T cells (ILT2), B cells (ILT2 and ILT4) and monomyelocytic cells (ILT2 and ILT4).
There is in vitro evidence that HLA-G has an immunomodulatory effect on peripheral lymphocytes. The membrane-bound form has been shown to protect cells from lysis by NK cells (Rouas Freiss et al., 1997), it inhibits the allo-proliferative response in a mixed lymphocyte culture (Riteau et al., 1999; Bainbridge et al., 2000a) and affects cytokine production (Maejima et al., 1997).
In the endometrium, the main population of leukocytes present are the NK cells. Their number gradually increases during the menstrual cycle, peaking at the time of implantation. When pregnancy occurs, the NK cells remain in the decidua and come into close contact with the invading trophoblast. Their abundant presence at the time of implantation and the expression of receptors for HLA-G suggest a role for NK cells by modulating implantation by interaction with HLA-G, present on the invading trophoblast.
Two functions of HLA-G in modulating uterine NK cells have been postulated. First, they might protect trophoblasts from NK cell-mediated lysis (Rouas Freiss et al., 1997). More recent data, however, suggest that this protection appears to be largely independent of HLA class I expression (Avril et al., 1999; King et al., 2000). Therefore, the second option is more likely, which is to modulate production of cytokines and angiogenic factors by uterine NK cells in order to alter trophoblast invasion and differentiation or tissue remodelling (Li et al., 2001). This would suggest a more finely tuned modulatory function for HLA-G rather than a strictly inhibitory function.
Cytokines that are produced by NK cells and/or T cells and that might play a role in implantation are interferon (IFN)-, vascular endothelial growth factor (VEGF), interleukin-3 (IL-3) and leukaemia inhibitory factor (LIF). During implantation, IFN- may play a dual role. It has been shown that a localized production of IFN- by uterine NK cells is necessary for vascular modification and decidual integrity and thereby contributes to normal pregnancy in mice (Ashkar et al., 2000). A more generalized IFN- response, however, is likely to be detrimental, since this was found to be associated with pregnancy disorders (Wegmann et al., 1993; Raghupathy, 1997). VEGF is an important growth factor involved in angiogenesis by affecting endothelial cells (Abulafia and Sherer, 1999) and was shown to be present in endometrium as well as in the decidua during gestation (Clark et al., 1998; Moller et al., 2001). Leukaemia inhibitory factor (LIF) has been shown to be an essential cytokine for implantation in mice (Stewart et al., 1992). In humans, LIF has been shown to be produced by uterine natural killer (uNK) cells as well as T cells (Piccinni et al., 1998). IL-3 has been shown to affect trophoblast implantation and development in vitro (Di Simone et al., 2000).
In the present study we investigated the effect of membrane-bound HLA-G on production of these various cytokines and proliferation of the uterine mononuclear cell population as a whole, and on uterine NK cells in particular. Since we were interested in cytokine production at the time of implantation, uterine cells were isolated from the endometrium of non-pregnant woman during the phase that the endometrium is receptive for implantation, i.e. 7 days after the LH surge.
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Materials and methods |
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Patients
Endometrial tissue was obtained from healthy non-pregnant women or women participating in an IVF programme who experienced total fertilization failure by a microcurettage using a pipelle de cornier (Prodimed, France) on day 7 after the LH surge in a natural cycle or 6 days after oocyte retrieval in the case of IVF treatment. All 13 women (eight IVF and five control) gave informed consent according to the Medical Ethical Review Committee of the University Medical Center Nijmegen.
Isolation of uterine mononuclear cells and uterine NK cells
Endometrial tissue (median weight 1 g, range 0.2–1.2 g) was mechanically disrupted by mincing between two scalpels and then filtered through a sieve. Mononuclear cells were isolated from the cell suspension by density centrifugation (Lymphoprep; Nycomed, Norway) yielding a median of 1.5x106 mononuclear cells per biopsy (range 0.5–3.4x106). The cellular composition was analysed by flow cytometry.
Uterine NK cells were purified from the uterine monolayer culture (UMC) population by negative selection (a cocktail of anti-CD3, CD4, CD19 and CD33 antibodies) using magnetic cell sorting (MACS) according to the manufacturer’s protocol (Miltenyi Biotech, Germany). Purity of the NK cell fraction was tested by flow cytometry and varied between 80 and 95%. In all cases the percentage of T cells was <2%. One representative example is shown in Figure 1.
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Flow cytometry
A total of 1x105 cells was stained directly using a combination of CD3-fluorescein isothiocyanate (FITC)/CD45-PE/CD56-Cy5 or CD16-FITC/CD3-PE/CD56-Cy5. Except CD56-Cy5 (Coulter Immunotech, France), all antibodies were purchased from Dako (Denmark). The samples were run on a Coulter Epics XL Flowcytometer (Beckman Coulter, USA), and 10 000 events were collected based on live lymphocyte cell gating as indicated by propidium iodide (PI, 5 µg/ml) staining. Isotype matched antibodies, usually below background staining, were used to define marker settings. Analysis of the data was performed using Coulter Epics Expo 32 software (Beckman Coulter).
Monoclonal antibodies and cell lines
The HLA-G specific antibody 56B was generated by immunization of Balb/c mice with a peptide corresponding to amino acids 138–158 of the 
2 domain of HLA-G (van Lierop et al., 2002). HLA-G specificity was shown by Western blot analysis and flow cytometry. Flow cytometric analysis of 721.221 cells transfected with HLA-G, HLA-B44 or HLA-E confirmed HLA-G specificity and showed no cross-reactivity with HLA-E (Figure 2). Similar results were obtained with K562 cells transfected with full-length HLA-G or HLA-E (kindly provided by Prof.-Dr E.H.Weiss, Munich, Germany, data not shown). The HLA-G specific antibody MEM-G/9 was obtained from Exbio (Prague, Czech Republic). The HLA-E specific antibody DT9 was a kind gift from Dr V.Braud (Valbonne, France).
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The HLA-A-, B-, C- and G-deficient B-cell line 721.221 was obtained from the American Type Culture Collection (ATCC, USA). 721.221 cells were stable transfected by electroporation with the full-length transcript of HLA-G1 inserted in the pNGV1 vector. HLA-G expression was confirmed by flow cytometry using the HLA-G specific monoclonal antibody MEM-G/9 or 56B as shown in Figure 2. HLA-B44 transfected 721.221 cells were a kind gift from Dr H.Dolstra (Nijmegen, The Netherlands). HLA-G1(Eneg)721.221 cells were a kind gift from Dr M.López-Botet (Madrid, Spain). These cells have been transfected with an HLA-G1 cDNA that has a mutated signal sequence that does not allow binding to HLA-E and thus prevents co-expression of HLA-E (Navarro et al., 1999). HLA-E 721.221 cells contain the HLA-E*0101 gene and the HLA-B8 signal sequence and were a kind gift from Dr V.Braud (Valbonne, France). Cells were continuously kept in culture in Roswell Park Memorial Institute (RPMI) 1640 medium with glutamax supplemented with pyruvate containing 100 IU/ml penicillin, 100 µg/ml streptomycin (all from Gibco, UK), 10% heat-inactivated fetal calf’s serum (FCS) and geneticin (1 µg/ml; Gibco). Cells were washed extensively before use in the co-cultures and HLA-G or B44 expression was checked for by FCM analysis using the monoclonal antibody W6/32.
Co-cultures
UMC or uterine NK cells were plated at 5x104 cells/well in triplicate in 96-well U-bottom microtitre plates (Greiner, Germany) in the presence of irradiated (100 Gy) 721.221 cells or HLA-G transfected 721.221 cells (5x104 cells/well) or HLA-B44 transfected or HLA-G1(Eneg) transfected 721.221. As a control, cells were plated in culture medium alone (RPMI 1640 with glutamax supplemented with pyruvate containing 100 U/ml penicillin, 100 µg/ml streptomycine (all from Gibco) and 10% heat-inactivated pooled human serum). In the case of blocking HLA-G, the anti-HLA-G monoclonal antibody (mAb) 56B was added to the wells at a concentration of 5 µg/ml. An isotype-matched irrelevant mAb was used as negative control. Analysis of the kinetics showed a peak in proliferation and IFN- production around day 5. Therefore, after 5 days incubation at 37°C in a humidified atmosphere containing 5% CO2, supernatant was harvested for cytokine measurements and subsequently 0.5 µCi [3H]TdR was added to each well. The plates were harvested the following day (day 6) using a Micromate 196 harvesting device (Canberra, USA) and counted in the Packard Matrix 96 Direct Beta counter (Canberra). The results are presented as the mean ± SD from triplicate wells.
Enzyme-linked immunosorbent assay (ELISA)
Cytokines were measured in cell culture supernatants. IFN- (Pelikine Compact human ELISA kit; CLB, The Netherlands), IL-3, VEGF (both from Biosource International, USA) and LIF (R&D systems, USA) were measured by sandwich ELISA. The VEGF ELISA only detects the VEGF-165 form and not PIGF. The assays were performed according to the supplier’s manual. The results were measured photometrically at 450 nm using an ELISA plate reader (Titertek Multiskan MCC/340). VEGF data were corrected for background production of VEGF by irradiated 721.221 cells or 721.221 cells transfected with mHLA-G. Data are mean of a triplicate.
Statistical analysis
Differences between groups were analysed for significance (P < 0.05) by a two-sided Student’s t-test or, in the case of three sample groups, by a one-way analysis of variance.
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Results |
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Membrane-bound HLA-G stimulates proliferation of uterine NK cells
To study the effect of membrane-bound HLA-G on the proliferation of uterine lymphocytes and in particular uterine NK cells, 721.221 cells transfected with HLA-G1 were used as stimulator cells in a mixed lymphocyte culture. 721.221 cells are HLA-A and B negative, but HLA class II positive and can thus function as allogeneic stimulator cells. The data show that expression of mHLA-G suppressed the allo-induced proliferation of UMC consisting of NK cells, T cells, B cells and monocytes/macrophages (Figure 3a, P < 0.0001). In four independent experiments this inhibition varied from 46 up to 100% as compared to cultures with non-transfected 721.221 cells. The inhibitory effect of HLA-G could at least partly be reversed by the addition of the anti-HLA-G monoclonal antibody 56B to the cultures (Figure 3a). Since the 721.221-HLA-G transfected cells express both HLA-G and HLA-E at the cell surface, we further confirmed HLA-G specificity of the effect by using the HLA-G(Eneg) 721.221 cell-line. This cell line was negative for HLA-E expression, as was shown by staining with HLA-E specific antibody DT9 (data not shown). Again, proliferation of UMC was inhibited by the HLA-G-expressing cells up to 80% in four independent experiments (Figure 3b, P < 0.005), clearly showing that the inhibition was induced by HLA-G.
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Furthermore, the inhibitory effect appeared not broadly class I specific, since the response to HLA-B44 transfected 721.221 cells was not strongly inhibited (Figure 3c), although in different experiments the strength of the response was variable.
In contrast to the overall inhibitory effect observed for the unfractionated population, mHLA-G stimulated proliferation of purified uterine NK cells (Figure 4a, P < 0.005). While purified uterine NK cells hardly proliferate on stimulation with untransfected 721.221 cells, expression of mHLA-G resulted in enhanced proliferation of this population. Again a similar effect was observed when the HLA-G(Eneg) 721.221 cells were used (Figure 4b, P < 0.05).
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Membrane-bound HLA-G stimulates IFN-
production by uterine NK cellsNext, we addressed the question of whether mHLA-G can affect cytokine production by UMC or purified uNK cells. Supernatants of co-cultures set up with UMC or purified uterine NK cells and mHLA-G transfected 721.221 cells were analysed by sandwich ELISA for IFN-
levels. Membrane-bound HLA-G significantly inhibited the 721.221-induced IFN- production of UMC (Figure 5a, P < 0.05, percentage inhibition ranging from 27 to 100% in four different experiments). Co-culture with HLA-B44 transfected 721.221 cells also lead to a slight reduction in IFN- production, although this was never as marked as for HLA-G. Notably and in line with the proliferation data, when purified uterine NK cells were used, an increase in IFN- was observed (Figure 5b, P < 0.05). For both UMC and purified uNK cells, similar data were obtained when using the HLA-G(Eneg) 721.221 cells (data not shown).
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Membrane bound HLA-G stimulates VEGF production
Besides IFN-
, the effect of mHLA-G was also evaluated for three other cytokines that potentially play a role in implantation and placentation and are produced by T cells and/or NK cells, i.e. VEGF, IL-3 and LIF. Regarding VEGF, our data show that UMC (Figure 6a, P < 0.005) as well as purified uterine NK cells (Figure 6b, P < 0.05) produce increased levels of VEGF upon co-culture with mHLA-G transfected 721.221 cells as compared to the untransfected 721.221 cells. Co-culture with HLA-B44 transfected 721.221 cells did not significantly affect VEGF production (Figure 6a).
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In response to untransfected 721.221 cells, UMC produced only very low levels of IL-3 (Figure 7). Co-culture with mHLA-G transfected 721.221 cells in all cases led to a further decrease in IL-3 production although the reduction in levels did not reach statistical significance (Figure 7a, P = 0.07). No IL-3 was found in co-cultures with purified uterine NK cells (Figure 7b). Again, similar data were obtained when using the HLA-G(Eneg) 721.221 transfectants (P < 0.05, data not shown) and no significant decrease was observed in co-cultures with HLA-B44 transfected 721.221 cells (Figure 7a).
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With respect to LIF, neither UMC nor purified uterine NK cells produced detectable levels of LIF upon stimulation with 721.221 cells or HLA-G transfected 721.221 cells.
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Discussion |
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In this study, we have shown that membrane-bound HLA-G promotes proliferation and IFN-
production of purified uterine NK cells derived from non-pregnant endometrium at the mid-luteal phase (day LH +7). Thus, our data reveal for the first time that mHLA-G can indeed stimulate specific functions of uterine NK cells that may positively contribute to implantation and decidualization. Studies on uterine lymphocytes so far have pointed only towards a role for mHLA-G in protection of the semi-allogeneic fetus from an attack by maternal NK and T cells. This was achieved by inhibition of NK cell cytotoxicity (Rouas Freiss et al., 1997) and down-modulation of Th1 type cytokine production (Kanai et al., 2001; Rieger et al., 2002). Up-regulation of the Th2 response by mHLA-G was found in peripheral lymphocytes, but was not observed for uterine lymphocytes (Kanai et al., 2001).
The increased IFN- production by uterine NK cells challenges the Th1/Th2 paradigm as proposed by Wegmann et al. (1993), which states that Th1-like cytokines are detrimental for successful pregnancy. In line with our data, several other groups have already shown the presence of both IFN- encoding mRNA (Saito et al., 1993; Jokhi et al., 1994) and IFN- protein (Jokhi et al., 1997) in uNK cells derived from pregnant women. Furthermore, receptors for IFN- are present on all first trimester cytotrophoblast populations, macrophages and vascular endothelial cells in the human decidua (Jokhi et al., 1997). In mice it has been shown that IFN- produced by uNK cells promotes the initiation of uterine vascular modification and decidual integrity and thereby contributes to a normal pregnancy (Ashkar and Croy, 1999; Ashkar et al., 2000). The finding that uNK cells produce IFN- in response to mHLA-G lends support to the idea that IFN- may play a role during the first stages of human pregnancy when HLA-G-expressing invading trophoblasts come into contact with uterine NK cells. The role of IFN- may be very localized, effective within a restricted time-frame and dependent on the expression levels, or, as Chaouat et al. (2002) stated with respect to the involvement of cytokines in pregnancy, ‘sequential windows and extreme complexity mixed with very precise timing and tuning’. A candidate receptor on uterine NK cells responsible for the up-regulation of IFN- production is KIR2DL4 (Ponte et al., 1999; Rajagopalan and Long, 1999). Triggering of this HLA-G binding receptor on resting NK cells has been shown to induce an increased IFN- production without affecting lytic function (Rajagopalan et al., 2001).
Because of the extremely limited material, we were not able to study the effect of 721.221 HLA-G transfectants on purified uterine T cells. However, it should be appreciated that in case of unfractionated UMC, the proliferation measured is the net result of the proliferation of T cells and NK cells. Using peripheral blood mononuclear cells it has been shown that the strong proliferative response of CD4+ T cells to 721.221 cells is inhibited by mHLA-G (Bainbridge et al., 2000a). Purified uterine NK cells show only limited proliferation. In the case of UMC, the stimulatory effect of mHLA-G on uterine NK cells is probably masked by the strong inhibition of a vigorous uterine T-cell response on the allogeneic HLA class II+ 721.221 cells. This remains to be confirmed by using uterine T cells.
The exact mechanism by which HLA-G induces proliferation of uterine NK cells remains speculative. So far two receptors have been identified that can bind to HLA-G and that are present on (uterine) NK cells, i.e. ILT2 and KIR2DL4. It remains to be determined whether the effect is induced directly via either of these receptors or that a yet unknown receptor plays a role in this effect. Furthermore, autocrine production of cytokines that affect NK cell proliferation may play a role. Decidual NK cells proliferate strongly in response to IL-15 and this cytokine can be produced by these cells themselves (Verma et al., 2000). Another important cytokine that plays a role in the induction of NK cell maturation, proliferation and IFN- production is IL-21 (Parrish-Novak et al., 2000; Strengell et al., 2003). However, it is not yet clear whether uterine NK cells can produce IL-21.
It is noteworthy that unfractionated UMC, including T cells, were inhibited in their IFN- production when co-cultured with mHLA-G transfected 721.221 cells. Apparently a generalized IFN- response in the uterus should be avoided and HLA-G protects against a too strong response. This down-modulation of IFN- production by mHLA-G has also been found by others when using unfractionated uterine leukocytes derived from pregnant endometrium (Kanai et al., 2001) as well as peripheral blood mononuclear cells (Maejima et al., 1997; Riteau et al., 1999; Bainbridge et al., 2000a). This indicates that the effects observed for membrane-bound HLA-G are not solely due to intrinsic properties of uterine lymphocytes but also extend to peripheral lymphocytes and lymphocytes that have already been in contact with fetal cells. Be that as it may, it cannot be excluded that differences exist at the single cell level or in the modulation of cytokines other than the few we have measured.
In our study we utilized mononuclear cells derived from non-pregnant endometrium at the time that it is receptive for implantation. Most other studies on the interaction between HLA-G and uterine cells have used cells from decidual tissue from elective abortions (Rouas Freiss et al., 1997; King et al., 2000; Kanai et al., 2001; Rieger et al., 2002). It has already been shown that decidual NK cells express different activation markers and adhesion molecules as compared to those from non-pregnant endometrium (Hill et al., 1986). Consequently, it is conceivable that the functional capacities of cells derived from non-pregnant endometrium differ since they have not yet been in contact with the invading trophoblasts and have not been affected by the altered hormone and cytokine levels that occur during pregnancy.
HLA-G specificity was shown by addition of anti-HLA-G monoclonal antibody to the co-culture of UMC and HLA-G transfected 721.221 cells, leading to reduction of the inhibitory effect of mHLA-G. To further exclude an effect of HLA-E we also used the HLA-G(Eneg) transfected 721.221 cells. Furthermore, the finding that proliferation and cytokine production of UMC was not inhibited by HLA-B44 expression on 721.221 cells indicates that the affect is not a broad characteristic of (classical) class I molecules. Nevertheless, this does not rule out the possibility that HLA-E plays a role in the uterus in modulation of the response. The leader peptide of HLA-G is capable of binding to HLA-E, leading to stabilization and surface expression of HLA-E in HLA-G transfected 721.221 cells. Although the receptor for HLA-E (CD94/NKG2) is present on practically all uterine NK cells, recent data indicated that HLA-E expressed on K562 cells does not affect IFN- production of decidual NK cells (Rieger et al., 2002). Very little is known so far on the effect of HLA-E on T cells, although it has been shown that HLA-E can be recognized through the ß T-cell receptor (Garcia et al., 2002). The fact that the HLA-G specific monoclonal antibody could not fully restore the response may indicate a role for HLA-E in the effect on T cells. The HLA-G transfected 721.221 cells mimic the in vivo situation in the sense that also on trophoblast cells HLA-G and HLA-E are expressed simultaneously (King et al., 2000). It is most likely that the combination of HLA-G and HLA-E loaded with HLA-G-derived nonamer peptide provides the unique signals for modulating local uterine immune responses.
In conclusion, our data suggest an active role for mHLA-G in modulating uterine NK cells that are present in the endometrium at the time that it is receptive for implantation. This indicates that mHLA-G is instrumental in active fine-tuning of the local immune response in order to promote successful implantation.
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Submitted on December 10, 2003; accepted on December 11, 2003.
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