A Specific Interferon (IFN)-stimulated Response Element of the Distal HLA-G Promoter Binds IFN-regulatory Factor 1 and Mediates Enhancement of This Nonclassical Class I Gene by IFN-β
2001; Elsevier BV; Volume: 276; Issue: 9 Linguagem: Inglês
10.1074/jbc.m008496200
ISSN1083-351X
AutoresSophie Lefebvre, Sonia Berrih‐Aknin, Francisco Adrián, Philippe Moreau, Sandrine Poëa, Luc Gourand, J Dausset, Edgardo D. Carosella, Pascale Paul,
Tópico(s)Cytokine Signaling Pathways and Interactions
ResumoType I interferons display a broad range of immunomodulatory functions. Interferon β increases gene expression at the transcriptional level through binding of factors to the interferon-stimulated response element (ISRE) within the promoters of interferon-inducible genes, such as HLA class I. Despite mutation of the class I ISRE sequence within the nonclassical HLA-G class I gene promoter, we show that interferon β enhances both transcription and cell surface expression of HLA-G in trophoblasts and amniotic and thymic epithelial cells that selectively express it in vivo. Deletion and mutagenesis analysis of a putative interferon-regulatory factor (IRF)-1 binding site within the HLA-G promoter show that HLA-G transactivation is mediated through an ISRE sequence 746 base pairs upstream from ATG, which is distinct from the interferon-responsive element described within proximal classical class I gene promoters. Electrophoretic mobility shift analysis and supershift analysis further demonstrate that interferon-responsive transcription factors, including IRF-1, specifically bind to the HLA-G ISRE. Our results provide evidence that IRF-1 binding to a functional ISRE within the HLA-G promoter mediates interferon β-induced expression of the HLA-G gene. These observations are of general interest considering the implication of HLA-G in mechanisms of immune escape involved in fetal-maternal tolerance and other immune privilege situations. Type I interferons display a broad range of immunomodulatory functions. Interferon β increases gene expression at the transcriptional level through binding of factors to the interferon-stimulated response element (ISRE) within the promoters of interferon-inducible genes, such as HLA class I. Despite mutation of the class I ISRE sequence within the nonclassical HLA-G class I gene promoter, we show that interferon β enhances both transcription and cell surface expression of HLA-G in trophoblasts and amniotic and thymic epithelial cells that selectively express it in vivo. Deletion and mutagenesis analysis of a putative interferon-regulatory factor (IRF)-1 binding site within the HLA-G promoter show that HLA-G transactivation is mediated through an ISRE sequence 746 base pairs upstream from ATG, which is distinct from the interferon-responsive element described within proximal classical class I gene promoters. Electrophoretic mobility shift analysis and supershift analysis further demonstrate that interferon-responsive transcription factors, including IRF-1, specifically bind to the HLA-G ISRE. Our results provide evidence that IRF-1 binding to a functional ISRE within the HLA-G promoter mediates interferon β-induced expression of the HLA-G gene. These observations are of general interest considering the implication of HLA-G in mechanisms of immune escape involved in fetal-maternal tolerance and other immune privilege situations. natural killer amniotic epithelial cell thymic epithelial cell interferon regulatory factor interferon-stimulated response element interferon γ-activated site interferon electrophoretic mobility shift assay signal transducers and activators of transcription monoclonal antibody reverse transcription-polymerase chain reaction polymerase chain reaction kilobase base pair(s) mean of fluorescence intensity IFN-stimulated gene factor 3 RNase protection assay HLA-G is defined as a nonclassical HLA class I antigen (1Kovats S. Main E.K. Librach C. Stubblebine M. Fisher S.J. DeMars R. Science. 1990; 248: 220-223Crossref PubMed Scopus (1215) Google Scholar, 2Ellis S.A. Sargent I.L. Redman C.W.G. McMichael A.J. Immunology. 1986; 59: 595-601PubMed Google Scholar) that was originally found to be restrictively expressed in the human placenta, where it is thought to play a role in maternal tolerance of the fetal semiallograft. HLA-G expression was further characterized on several placental cell types such as extravillous cytotrophoblasts, amniocytes, or endothelial cells of chorionic vessels and also on subsets of thymic epithelial cells (3Le Bouteiller P. Blaschitz A. Immunol. Rev. 1999; 167: 233-244Crossref PubMed Scopus (168) Google Scholar). HLA-G expression allows down-regulation of both NK1and T lymphocyte cytolytic functions (4Rouas-Freiss N. Khalil-Daher I. Riteau B. Menier C. Paul P. Dausset J. Carosella E. Semin. Cancer Biol. 1999; 9: 3-12Crossref PubMed Scopus (68) Google Scholar) through interaction with killing inhibitory receptors, namely p49/KIR2DL4, ILT2, and ILT4 (5Lopez-Botet M. Bellon T. Llano M. Navarro F. Garcia P. De Miguel M. Hum. Immunol. 2000; 61: 7-17Crossref PubMed Scopus (95) Google Scholar). The capacity of HLA-G leader peptides to stabilize surface expression of nonclassical HLA-E antigens also indirectly contributes to modulate cytolytic activity mediated by the widely expressed CD94/NKG2 receptors (6Llano M. Lee N. Navarro F. Garcia P. Albar J.P. Geraghty D.E. Lopez-Botet M. Eur. J. Immunol. 1998; 28: 2854-2863Crossref PubMed Scopus (320) Google Scholar). HLA-G associates with a wide array of nonamer peptides (7Lee N. Malacko A.R. Ishitani A. Chen M.C. Bajorath J. Marquardt H. Geraghty D.E. Immunity. 1995; 3: 591-600Abstract Full Text PDF PubMed Scopus (296) Google Scholar) and binds to the CD8 T-cell coreceptor (8Sanders S.K. Giblin P.A. Kavatas P. J. Exp. Med. 1991; 174: 737-740Crossref PubMed Scopus (119) Google Scholar, 9Gao G.F. Willcox B.E. Wyer J.R. Boulter J.M. O'Callaghan C.A. Maenaka K. Stuart D.I. Jones E.Y. Van Der Merwe P.A. Bell J.I. Jakobsen B.K. J. Biol. Chem. 2000; 275: 15232-15238Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). Other immunomodulatory roles, such as its capacity to elicit a T-cell receptor-restricted response in transgenic mice (10Horuzsko A. Antoniou J. Tomlinson P. Portik-Dobos V. Mellor A.L. Int. Immunol. 1997; 9: 645-653Crossref PubMed Scopus (44) Google Scholar), to trigger apoptosis of activated T and NK cells bearing the CD8 molecule (11Fournel S. Aguerre-Girr M. Huc X. Lenfant F. Alam A. Toubert A. Bensussan A. Le Bouteiller P. J. Immunol. 2000; 164: 6100-6104Crossref PubMed Scopus (424) Google Scholar), to impair NK cell migration (12Dorling A. Monk N.J. Lechler R.I. Eur. J. Immunol. 2000; 30: 586-593Crossref PubMed Scopus (88) Google Scholar), and to modulate cytokine (13Hamai Y. Fujii T. Yamashita T. Miki A. Hyodo H. Kozuma S. Geraghty D.E. Taketani Y. Am. J. Reprod. Immunol. 1999; 41: 153-158Crossref PubMed Scopus (26) Google Scholar, 14Maejima M. Fujii T. Kozuma S. Okai T. Shibata Y. Taketani Y. Am. J. Reprod. Immunol. 1997; 38: 79-82Crossref PubMed Scopus (84) Google Scholar) or the function of B or myelomonocytic cells bearing killing inhibitory receptors, have also been evoked. Tissue-specific patterns of HLA-G expression and their frequent alteration in pathological situations such as pregnancy disorders (15Goldman-Wohl D.S. Ariel I. Greenfield C. Hochner-Celnikier D. Cross J. Fisher S. Yagel S. Mol. Hum. Reprod. 2000; 6: 88-95Crossref PubMed Scopus (194) Google Scholar), viral infections (16Onno M. Pangault C. Le Friec G. Guilloux V. Andre P. Fauchet R. J. Immunol. 2000; 164: 6426-6434Crossref PubMed Scopus (146) Google Scholar, 17Schust D.J. Hill A.B. Ploegh H.L. J. Immunol. 1996; 157: 3375-3380PubMed Google Scholar, 18Schust D. Tortorella D. Seebach J. Phan C. Ploegh H. J. Exp. Med. 1998; 188: 497-503Crossref PubMed Scopus (123) Google Scholar, 19Jun Y. Kim E. Jin M. Sung H.C. Han H. Geraghty D.E. Ahn K. J. Immunol. 2000; 164: 805-811Crossref PubMed Scopus (95) Google Scholar), tumors (20Paul P. Rouas-Freiss N. Khalil-Daher I. Moreau P. Riteau B. Le Gal F.A. Avril M.F. Dausset J. Guillet J.G. Carosella E.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 4510-4515Crossref PubMed Scopus (387) Google Scholar, 21Adrian-Cabestre F. Lefebvre S. Moreau P. Rouas-Freiss N. Dausset J. Carosella E.D. Paul P. Semin. Cancer Biol. 1999; 9: 27-36Crossref PubMed Scopus (36) Google Scholar, 22Paul P. Adrian Cabestre F. Le Gal F.A. Khalil-Daher I. Le Danff C. Schmid M. Mercier S. Avril M.-F. Dausset J. Guillet J.-G. Carosella E.D. Cancer Res. 1999; 59: 1954-1960PubMed Google Scholar, 23Fukushima Y. Oshika Y. Nakamura M. Tokunaga T. Hatanaka H. Abe Y. Yamazaki H. Kijima H. Ueyama Y. Tamaoki N. Int. J. Mol. Med. 1998; 2: 349-351PubMed Google Scholar, 24Pangault C. Amiot L. Caulet-Maugendre S. Brasseur F. Burtin F. Guilloux V. Drenou B. Fauchet R. Onno M. Tissue Antigens. 1999; 53: 335-346Crossref PubMed Scopus (58) Google Scholar), or transplantation (25Lila N. Carpentier A. Amrein A.C. Khalil-Daher I. Dausset J. Carosella E. Lancet. 2000; 355: 2138Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar) may modulate the mounting of an efficient immune response and thus provide an additional mechanism to escape immune surveillance.Interferons are classified in a family of related cytokines, type I (IFN-α, -β, -ω, and -τ) and type II (IFN-γ) interferons, which mediate diverse functions including antiviral, antiproliferative, and immunomodulatory activities. Type I interferons are produced by many cell types (e.g. macrophages, T cells, keratinocytes, and Langerhans cells) in response to viral or bacterial infection and tumors. They display pleiotropic effects on the immune system, including stimulation of NK cells and macrophage activation, T-cell activation and survival, and up-regulation of various genes such as IFN-γ and major histocompatibility complex class I (26Hunter C.A. Gabriel K.E. Radzanowski T. Neyer L.E. Remington J.S. Immunol. Lett. 1997; 59: 1-5Crossref PubMed Scopus (86) Google Scholar). The cascade of events that yield to IFN type I induction involves activation of Jak/STAT transduction pathways and transactivation of inducible gene promoter through the ISRE regulatory element, a binding site for ISGF3 (IFN-stimulated gene factor 3) or IRFs (27Levy D.E. Kessler D.S. Pine R. Reich N. Darnell Jr., J.E. Genes Dev. 1988; 2: 383-393Crossref PubMed Scopus (382) Google Scholar, 28Darnell Jr., J.E. Kerr I.M. Stark G.R. Science. 1994; 264: 1415-1421Crossref PubMed Scopus (4950) Google Scholar). After binding to its receptor, IFN type I induces translocation of activated STAT1 and STAT2 into the nucleus and formation of a heterotrimeric complex containing p48/ISGF3γ (ISGF3). Among transcription factors belonging to the IRF family, IRF-1 and IRF-2 are secondary IFN response factors that interact mainly with ISRE to activate or repress target promoter activity (29Harada H. Fujita T. Miyamoto M. Kimura Y. Maruyama M. Furia A. Miyata T. Taniguchi T. Cell. 1989; 58: 729-739Abstract Full Text PDF PubMed Scopus (798) Google Scholar).Another well-characterized IFN cis-acting regulatory element is the IFN-γ activation site (GAS), which rather mediates the immediate response of several genes to IFN-γ (30Lew D.J. Decker T. Strehlow I. Darnell J.E. Mol. Cell. Biol. 1991; 11: 182-191Crossref PubMed Scopus (235) Google Scholar).The pattern of HLA-G expression is tightly regulated due to cell-specific transcriptional control, but the regulatory pathways controlling its tissue-specific transactivation remain to be established. HLA-G gene expression can be activated by interleukin 10 (31), glucocorticoids, or stress treatment (32Ibrahim E.C. Morange M. Dausset J. Carosella E. Paul P. Cell Stress Chaperones. 2000; 5: 207-218Crossref PubMed Scopus (76) Google Scholar) independently of classical HLA class I genes or by IFNs (33Yang Y. Geraghty D.E. Hunt J.S. J. Reprod. Immunol. 1995; 29: 179-195Crossref PubMed Scopus (62) Google Scholar, 34Yang Y. Chu W. Geraghty D.E. Hunt J.S. J. Immunol. 1996; 156: 4224-4231PubMed Google Scholar, 35Chu W. Yang Y. Geraghty D.E. Hunt J.S. J. Reprod. Immunol. 1999; 42: 1-15Crossref PubMed Scopus (32) Google Scholar, 36Lefebvre S. Moreau P. Guiard V. Ibrahim E.C. Adrian-Cabestre F. Menier C. Dausset J. Carosella E.D. Paul P. J. Reprod. Immunol. 1999; 43: 213-224Crossref PubMed Scopus (56) Google Scholar), despite deleterious mutations within the HLA-G promoter of criticalcis-acting regulatory elements involved in the constitutive and interferon-inducible transcription of HLA-class I genes (enhancer-A, ISRE, and site α) (37Gobin S.J.P. Keijsers V. Van Zutphen M. Van den Elsen P.J. J. Immunol. 1998; 161: 2276-2283PubMed Google Scholar, 38Gobin S.J.P. van Zutphen M. Woltman A. Van den Elsen P.J. J. Immunol. 1999; 163: 1428-1434PubMed Google Scholar, 39Gobin S.J. Peijnenburg A. Keijsers V. van den Elsen P.J. Immunity. 1997; 6: 601-611Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar).Our study aimed at identifying the molecular mechanism by which IFN-β enhances both transcription and cell surface expression of the nonclassical HLA-G antigen in trophoblast, amnion, and thymus-derived epithelial cells that also express it in vivo. We report that IFN-β up-regulates HLA-G transcription through promoter transactivation and binding of IFN-responsive factors, including IRF-1, to a functional ISRE mapped at 746 bp from the ATG, within the HLA-G promoter.DISCUSSIONA previous study reported the ability of IFN-β to enhance levels of HLA-G surface antigens, but these data remained preliminary because they were only reported on transfected mouse fibroblasts. Although IFN-β was identified as a potent inductor of HLA-G transcription in other cell types (33Yang Y. Geraghty D.E. Hunt J.S. J. Reprod. Immunol. 1995; 29: 179-195Crossref PubMed Scopus (62) Google Scholar, 34Yang Y. Chu W. Geraghty D.E. Hunt J.S. J. Immunol. 1996; 156: 4224-4231PubMed Google Scholar, 35Chu W. Yang Y. Geraghty D.E. Hunt J.S. J. Reprod. Immunol. 1999; 42: 1-15Crossref PubMed Scopus (32) Google Scholar), the regulatory pathways yielding to this transactivation were not elucidated. Indeed, little is known about sequences and factors that participate in transactivation of the HLA-G promoter, in which most of the conserved regulatory DNA elements involved in the constitutive and cytokine-induced expression of the HLA class I genes are disrupted and nonfunctional.Our findings represent the first evidence of HLA-G modulation and overall IFN-β-mediated up-regulation of HLA class I cell surface expression in amnion and thymic epithelial cells expressing HLA-G. We also show that IFN-β-mediated enhancement of the level of HLA-G surface antigens was comparable to that of classical HLA class I surface antigens and was correlated to an overall enhancement of the levels of HLA-G transcripts. The extent of up-regulation of HLA-G transcript levels we observed in IFN-β-treated primary cells, cell lines, and trophoblast tissue was in agreement with the 2–2.5-fold enhancement reported previously and may not be attributed to increased stability of mRNA but rather to stimulation of the HLA-G transcription rate (35Chu W. Yang Y. Geraghty D.E. Hunt J.S. J. Reprod. Immunol. 1999; 42: 1-15Crossref PubMed Scopus (32) Google Scholar). Our results confirm that IFN-β is a potent inducer of HLA-G transcription, which may explain the effect observed at the surface of HLA-G-expressing cells, although a posttranscriptional effect of IFN-β on HLA-G enhancement cannot be excluded.We further elucidated part of the regulatory mechanisms involved in IFN-β induction of HLA-G transcription. We have identified a functional ISRE at position −746 bp from the ATG within the distal HLA-G promoter, and we demonstrate that this site is necessary to confer IFN-β transactivation of the 1.4-kb HLA-G gene promoter fragment. This ISRE does not appear to be conserved among other classical HLA class I promoters and could represent a locus-specific pathway of IFN-β-mediated induction of the nonclassical HLA-G class I antigen. We also demonstrate that the GAS element, lying downstream of the ISRE, does not play a role in IFN-β transactivation of HLA-G.Previous studies on the transactivating effect of the ISRE element upon IFN stimulation point out that both enhancer A and site α are crucial for maximal induction of HLA class I genes through the ISRE (37Gobin S.J.P. Keijsers V. Van Zutphen M. Van den Elsen P.J. J. Immunol. 1998; 161: 2276-2283PubMed Google Scholar, 39Gobin S.J. Peijnenburg A. Keijsers V. van den Elsen P.J. Immunity. 1997; 6: 601-611Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar). The nonclassical HLA-E also contains a specific IFN-γ response region constituted of two adjacent cis-acting regulatory elements, both of which are required to mediate the full response to IFN-γ (48Gustafson K.S. Ginder G.D. J. Biol. Chem. 1996; 271: 20035-20046Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). No adjacent cooperative sequence seems to be required for full induction by IFN-β through the functional ISRE within the HLA-G promoter, which identifies the particular nature of IFN-β-mediated HLA-G induction. The level of IFN-β-mediated induction of HLA-G surface antigens was quite well correlated to the level of HLA-G promoter transactivation through the −746 ISRE and was similar to that reported using a transfected HLA-G 6.0-kb fragment containing the 1.4-kb promoter fragment and 3′ sequences (35Chu W. Yang Y. Geraghty D.E. Hunt J.S. J. Reprod. Immunol. 1999; 42: 1-15Crossref PubMed Scopus (32) Google Scholar). Nevertheless, we cannot exclude the presence of other functional IFN-responsive sites within the HLA-G gene.HLA-G expression can be induced by IFN-α and IFN-γ in transfected mouse fibroblasts (35Chu W. Yang Y. Geraghty D.E. Hunt J.S. J. Reprod. Immunol. 1999; 42: 1-15Crossref PubMed Scopus (32) Google Scholar). Whether the functional ISRE is able to mediate transcriptional activation of HLA-G upon both type I IFNs remains to be verified. Interestingly, we have previously reported a lack of activation of the 1.4-kb HLA-G promoter fragment in IFN-γ-treated JEG-3 or in IFN-γ-treated Tera-2 cells (36Lefebvre S. Moreau P. Guiard V. Ibrahim E.C. Adrian-Cabestre F. Menier C. Dausset J. Carosella E.D. Paul P. J. Reprod. Immunol. 1999; 43: 213-224Crossref PubMed Scopus (56) Google Scholar, 37Gobin S.J.P. Keijsers V. Van Zutphen M. Van den Elsen P.J. J. Immunol. 1998; 161: 2276-2283PubMed Google Scholar) that displayed a 3-fold enhancement of HLA-G promoter activation upon treatment with IFN-β (data not shown). This could suggest that the ISRE mediating the IFN-β response within the HLA-G promoter is not involved in IFN-γ transactivation of HLA-G or requires additional cooperative regulatory elements. These results point out that differential and overlapping mechanisms, including several regulatory pathways and cooperative interactions between cellular factors involved in the specific response to IFNs, regulate IFN-α, -β, and-γ transactivation of HLA-G and other HLA class I genes.We further provide evidence that IRF-1 binds to the functional ISRE within the HLA-G promoter in response to IFN-β and may thus represent a key factor in the regulation of the HLA-G gene in trophoblast, amnion, and thymus-derived cells. Accordingly, IRF-1 is described as the principal transcription factor binding to the ISRE within the major histocompatibility complex class I promoter (49Hobart M. Ramassar V. Goes N. Urmson J. Halloran P.F. J. Immunol. 1997; 158: 4260-4269PubMed Google Scholar). Supershift analysis failed to identify other known ISRE-binding proteins such as IRF-2, p48, or STAT1α. An altered activity of the p48/ISGF3γ subunit of the ISGF3 factor has been reported in trophoblast cells (47Cross J.C. Lam S. Yagel S. Werb Z. Biol. Reprod. 1999; 60: 312-321Crossref PubMed Scopus (16) Google Scholar). STAT1-containing complexes binding to HLA class I ISREs were not detected in IFN-γ-treated HeLa cells, unlike such GAS-binding complexes (38Gobin S.J.P. van Zutphen M. Woltman A. Van den Elsen P.J. J. Immunol. 1999; 163: 1428-1434PubMed Google Scholar), suggesting that ISRE-protein complexes would be barely detectable in supershift experiments.In addition to playing essential roles in IFN responses, IRF-1 proteins are involved in other regulatory processes, i.e. cell cycle regulation, tumor suppression, oncogenic activities, apoptosis, and development and function of immune effector cells (50Duncan G.S. Mittrucker H.W. Kagi D. Matsuyama T. Mak T.W. J. Exp. Med. 1996; 184: 2043-2048Crossref PubMed Scopus (110) Google Scholar, 51Lohoff M. Ferrick D. Mittrucker H.W. Duncan G.S. Bischof S. Rollinghoff M. Mak T.W. Immunity. 1997; 6: 681-689Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar). Interleukin 2 and interleukin 12 have been shown to directly induce IRF-1 gene expression in human T and NK cells (52Galon J. Sudarshan C. Ito S. Finbloom D. O'Shea J.J. J. Immunol. 1999; 162: 7256-7262PubMed Google Scholar). Whether these cytokines that promote cell-mediated immune response could also enhance HLA-G expression through binding of IRF-1 to ISRE should be further investigated in immunocompetent cells.Type I interferons are highly involved in both the innate and specific host protective response, such as the T-cell IFN-γ response to viral infection (53Muller U. Steinhoff U. Reis L.F. Hemmi S. Pavlovic J. Zinkernagel R.M. Aguet M. Science. 1994; 264: 1918-1921Crossref PubMed Scopus (1975) Google Scholar, 54Cousens L.P. Peterson R. Hsu S. Dorner A. Altman J.D. Ahmed R. Biron C.A. J. Exp. Med. 1999; 189: 1315-1328Crossref PubMed Scopus (251) Google Scholar, 55Durbin J.E. Fernandez-Sesma A. Lee C.K. Rao T.D. Frey A.B. Moran T.M. Vukmanovic S. Garcia-Sastre A. Levy D.E. J. Immunol. 2000; 164: 4220-4228Crossref PubMed Scopus (231) Google Scholar). Facing this, viruses have evolved numerous strategies to subvert host defenses, including modulation of major histocompatibility complex class I expression or mimicking host cell genes such as IRF-1 or ILT2 (56Alcami A. Koszinowski U.H. Immunol. Today. 2000; 21: 447-455Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar). Alteration of HLA-G or locus-specific class I gene expression may also interfere in the balance between escape from cytotoxic T lymphocytes and maintenance of protection from NK cells (16Onno M. Pangault C. Le Friec G. Guilloux V. Andre P. Fauchet R. J. Immunol. 2000; 164: 6426-6434Crossref PubMed Scopus (146) Google Scholar, 17Schust D.J. Hill A.B. Ploegh H.L. J. Immunol. 1996; 157: 3375-3380PubMed Google Scholar, 18Schust D. Tortorella D. Seebach J. Phan C. Ploegh H. J. Exp. Med. 1998; 188: 497-503Crossref PubMed Scopus (123) Google Scholar, 19Jun Y. Kim E. Jin M. Sung H.C. Han H. Geraghty D.E. Ahn K. J. Immunol. 2000; 164: 805-811Crossref PubMed Scopus (95) Google Scholar, 57Tomasec P. Braud V.M. Rickards C. Powell M.B. McSharry B.P. Gadola S. Cerundolo V. Borysiewicz L.K. McMichael A.J. Wilkinson G.W. Science. 2000; 287: 1031-1033Crossref PubMed Scopus (507) Google Scholar). Given that IFN-β is produced in virally infected trophoblast and amnion (58Carvalho A.F. Santos J.R. Gentz R. Bonjardim C.A. Golgher R.R. Ferreira P.C. Kroon E.G. Placenta. 1998; 19: 307-314Crossref PubMed Scopus (8) Google Scholar, 59Paradowska E. Blach-Olszewska Z. Sender J. Jarosz W. J. Interferon Cytokine Res. 1996; 16: 941-948Crossref PubMed Scopus (41) Google Scholar), specific pathways of HLA-G modulation could permit infected cells to block NK and T-cell responses, as seen during maternal-fetal transmission of human cytomegalovirus (60Halwachs-Baumann G. Wilders-Truschnig M. Desoye G. Hahn T. Kiesel L. Klingel K. Rieger P. Jahn G. Sinzger C. J. Virol. 1998; 72: 7598-7602Crossref PubMed Google Scholar) or human immunodeficiency virus. Alternatively, lysis of infected material could be triggered by CD94/NKG2C receptors through HLA-E surface expression or by HLA-G-restricted T-cell Receptor and thus prevent pathogen spreading from the placental cells to the fetus. IFN-β-mediated HLA-G up-regulation in TECs could also affect selection of the thymic repertoire.Type I interferons are used in the treatment of several human pathologies such as infectious diseases, multiple sclerosis, or tumors. Whether the nonclassical HLA-G molecule is up-regulated during IFN treatment or plays a role in favoring or impairing immune responses to such therapeutic approaches also remains an interesting issue. Indeed, analysis of aberrant expression of HLA-G combined with loss of classical HLA molecules on melanoma cells could have important practical implications for the selection of patients likely not to benefit from interferon α therapy (61Wagner S.N. Rebmann V. Willers C.P. Grosse-Wilde H. Goos M. Lancet. 2000; 356: 220-221Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar).Our results point out that IFN-β-mediated enhancement of HLA-G expression may occur as a way to refine modulation of immune responses during pregnancy, thymic involution, or IFN-β treatment of autoimmune diseases and tumor progression. HLA-G is defined as a nonclassical HLA class I antigen (1Kovats S. Main E.K. Librach C. Stubblebine M. Fisher S.J. DeMars R. Science. 1990; 248: 220-223Crossref PubMed Scopus (1215) Google Scholar, 2Ellis S.A. Sargent I.L. Redman C.W.G. McMichael A.J. Immunology. 1986; 59: 595-601PubMed Google Scholar) that was originally found to be restrictively expressed in the human placenta, where it is thought to play a role in maternal tolerance of the fetal semiallograft. HLA-G expression was further characterized on several placental cell types such as extravillous cytotrophoblasts, amniocytes, or endothelial cells of chorionic vessels and also on subsets of thymic epithelial cells (3Le Bouteiller P. Blaschitz A. Immunol. Rev. 1999; 167: 233-244Crossref PubMed Scopus (168) Google Scholar). HLA-G expression allows down-regulation of both NK1and T lymphocyte cytolytic functions (4Rouas-Freiss N. Khalil-Daher I. Riteau B. Menier C. Paul P. Dausset J. Carosella E. Semin. Cancer Biol. 1999; 9: 3-12Crossref PubMed Scopus (68) Google Scholar) through interaction with killing inhibitory receptors, namely p49/KIR2DL4, ILT2, and ILT4 (5Lopez-Botet M. Bellon T. Llano M. Navarro F. Garcia P. De Miguel M. Hum. Immunol. 2000; 61: 7-17Crossref PubMed Scopus (95) Google Scholar). The capacity of HLA-G leader peptides to stabilize surface expression of nonclassical HLA-E antigens also indirectly contributes to modulate cytolytic activity mediated by the widely expressed CD94/NKG2 receptors (6Llano M. Lee N. Navarro F. Garcia P. Albar J.P. Geraghty D.E. Lopez-Botet M. Eur. J. Immunol. 1998; 28: 2854-2863Crossref PubMed Scopus (320) Google Scholar). HLA-G associates with a wide array of nonamer peptides (7Lee N. Malacko A.R. Ishitani A. Chen M.C. Bajorath J. Marquardt H. Geraghty D.E. Immunity. 1995; 3: 591-600Abstract Full Text PDF PubMed Scopus (296) Google Scholar) and binds to the CD8 T-cell coreceptor (8Sanders S.K. Giblin P.A. Kavatas P. J. Exp. Med. 1991; 174: 737-740Crossref PubMed Scopus (119) Google Scholar, 9Gao G.F. Willcox B.E. Wyer J.R. Boulter J.M. O'Callaghan C.A. Maenaka K. Stuart D.I. Jones E.Y. Van Der Merwe P.A. Bell J.I. Jakobsen B.K. J. Biol. Chem. 2000; 275: 15232-15238Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). Other immunomodulatory roles, such as its capacity to elicit a T-cell receptor-restricted response in transgenic mice (10Horuzsko A. Antoniou J. Tomlinson P. Portik-Dobos V. Mellor A.L. Int. Immunol. 1997; 9: 645-653Crossref PubMed Scopus (44) Google Scholar), to trigger apoptosis of activated T and NK cells bearing the CD8 molecule (11Fournel S. Aguerre-Girr M. Huc X. Lenfant F. Alam A. Toubert A. Bensussan A. Le Bouteiller P. J. Immunol. 2000; 164: 6100-6104Crossref PubMed Scopus (424) Google Scholar), to impair NK cell migration (12Dorling A. Monk N.J. Lechler R.I. Eur. J. Immunol. 2000; 30: 586-593Crossref PubMed Scopus (88) Google Scholar), and to modulate cytokine (13Hamai Y. Fujii T. Yamashita T. Miki A. Hyodo H. Kozuma S. Geraghty D.E. Taketani Y. Am. J. Reprod. Immunol. 1999; 41: 153-158Crossref PubMed Scopus (26) Google Scholar, 14Maejima M. Fujii T. Kozuma S. Okai T. Shibata Y. 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