A homodimeric complex of HLA‐G on normal trophoblast cells modulates antigen‐presenting cells via LILRB1

Abstract

In healthy individuals, the non‐classical MHC molecule HLA‐G is only expressed on fetal trophoblast cells that invade the decidua during placentation. We show that a significant proportion of HLA‐G at the surface of normal human trophoblast cells is present as a disulphide‐linked homodimer of the conventional β 2 m‐associated HLA‐I complex. HLA‐G is a ligand for leukocyte immunoglobulin‐like receptors (LILR), which bind much more efficiently to dimeric HLA‐G than to conventional HLA‐I molecules. We find that a LILRB1‐Fc fusion protein preferentially binds the dimeric form of HLA‐G on trophoblast cells. We detect LILRB1 expression on decidual myelomonocytic cells; therefore, trophoblast HLA‐G may modulate the function of these cells. Co‐culture with HLA‐G + cells does not inhibit monocyte‐derived dendritic cell up‐regulation of HLA‐DR and costimulatory molecules on maturation, but did increase production of IL‐6 and IL‐10. Furthermore, proliferation of allogeneic lymphocytes was inhibited by HLA‐G binding to LILRB1/2 on responding antigen‐presenting cells (APC). As HLA‐G is the only HLA‐I molecule that forms β 2 m‐associated dimers with increased avidity for LILRB1, this interaction could represent a placental‐specific signal to decidual APC. We suggest that the placenta is modulating maternal immune responses locally in the uterus through HLA‐G, a trophoblast‐specific, monomorphic signal present in almost every pregnancy. See accompanying commentary: http://dx.doi.org/10.1002/eji.200737515

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References 68

1. 1.

   McMaster MT, Librach CL, Zhou Y, Lim KH, Janatpour MJ, DeMars R, Kovats S, et al. Human placental HLA-G expression is restricted to differentiated cytotrophoblasts. J. Immunol. 1995;154:3771-3778.

   Not in our library

2. 2.

   Loke YW, King A, Burrows T, Gardner L, Bowen M, Hiby S, Howlett S, et al. Evaluation of trophoblast HLA-G antigen with a specific monoclonal antibody. Tissue Antigens. 1997;50:135-146.

   Not in our library10.1111/j.1399-0039.1997.tb02852.x

3. 3.

   Hiby SE, King A, Sharkey AM, Loke YW. Molecular studies of trophoblast HLA-G: Polymorphism, isoforms, imprinting and expression in preimplantation embryo. Tissue Antigens. 1999;53:1-13.

   Not in our library10.1034/j.1399-0039.1999.530101.x

4. 4.

   Blaschitz A, Juch H, Volz A, Hutter H, Daxboeck C, Desoye G, Dohr G. The soluble pool of HLA-G produced by human trophoblasts does not include detectable levels of the intron 4-containing HLA-G5 and HLA-G6 isoforms. Mol. Hum. Reprod. 2005;11:699-710.

   Not in our library10.1093/molehr/gah185

5. 5.

   Davis DM, Reyburn HT, Pazmany L, Chiu I, Mandelboim O, Strominger JL. Impaired spontaneous endocytosis of HLA-G. Eur. J. Immunol. 1997;27:2714-2719.

   Not in our library10.1002/eji.1830271035

6. 6.

   Bainbridge DR, Ellis SA, Sargent IL. Little evidence of HLA-G mRNA polymorphism in Caucasian or Afro-Caribbean populations. J. Immunol. 1999;163:2023-2027.

   Not in our library

7. 7.

   Ishitani A, Kishida M, Sageshima N, Yashiki S, Sonoda S, Hayami M, Smith AG, Hatake K. Re-examination of HLA-G polymorphism in African Americans. Immunogenetics. 1999;49:808-811.

   Not in our library10.1007/s002510050555

8. 8.

   Park B, Lee S, Kim E, Chang S, Jin M, Ahn K. The truncated cytoplasmic tail of HLA-G serves a quality-control function in post-ER compartments. Immunity. 2001;15:213-224.

   Not in our library10.1016/s1074-7613(01)00179-0

9. 9.

   Clements CS, Kjer-Nielsen L, Kostenko L, Hoare HL, Dunstone MA, Moses E, Freed K, et al. Crystal structure of HLA-G: A nonclassical MHC class I molecule expressed at the fetal-maternal interface. Proc. Natl. Acad. Sci. USA. 2005;102:3360-3365.

   Not in our library10.1073/pnas.0409676102

10. 10.

    Ishitani A, Sageshima N, Lee N, Dorofeeva N, Hatake K, Marquardt H, Geraghty DE. Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition. J. Immunol. 2003;171:1376-1384.

    Not in our library10.4049/jimmunol.171.3.1376

11. 11.

    Moffett-King A. Natural killer cells and pregnancy. Nat. Rev. Immunol. 2002;2:656-663.

    Not in our library10.1038/nri886

12. 12.
    Activation of NK Cells by an Endocytosed Receptor for Soluble HLA-G · 2005

    No notice
13. 13.

    Borges L, Cosman D. LIRs/ILTs/MIRs, inhibitory and stimulatory Ig-superfamily receptors expressed in myeloid and lymphoid cells. Cytokine Growth Factor Rev. 2000;11:209-217.

    Not in our library10.1016/s1359-6101(00)00007-1

14. 14.

    Navarro F, Llano M, Bellon T, Colonna M, Geraghty DE, Lopez-Botet M. The ILT2 and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. Eur. J. Immunol. 1999;29:277-283.

    Not in our library10.1002/(sici)1521-4141(199901)29:01<277::aid-immu277>3.0.co;2-4

15. 15.

    Willcox BE, Thomas LM, Bjorkman PJ. Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor. Nat. Immunol. 2003;4:913-919.

    Not in our library10.1038/ni961

16. 16.

    Shiroishi M, Tsumoto K, Amano K, Shirakihara Y, Colonna M, Braud VM, Allan DS, et al. Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc. Natl. Acad. Sci. USA. 2003;100:8856-8861.

    Not in our library10.1073/pnas.1431057100

17. 17.

    Boyson JE, Erskine R, Whitman MC, Chiu M, Lau JM, Koopman LA, Valter MM, et al. Disulfide bond-mediated dimerization of HLA-G on the cell surface. Proc. Natl. Acad. Sci. USA. 2002;99:16180-16185.

    Not in our library10.1073/pnas.212643199

18. 18.

    Gonen-Gross T, Achdout H, Gazit R, Hanna J, Mizrahi S, Markel G, Goldman-Wohl D, et al. Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function. J. Immunol. 2003;171:1343-1351.

    Not in our library10.4049/jimmunol.171.3.1343

19. 19.

    Gonen-Gross T, Achdout H, Arnon TI, Gazit R, Stern N, Horejsi V, Goldman-Wohl D, et al. The CD85J/leukocyte inhibitory receptor-1 distinguishes between conformed and beta 2-microglobulin-free HLA-G molecules. . J. Immunol. 2005;175:4866-4874.

    Not in our library10.4049/jimmunol.175.8.4866

20. 20.

    Shiroishi M, Kuroki K, Ose T, Rasubala L, Shiratori I, Arase H, Tsumoto K, et al. Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer. J. Biol. Chem. 2006;281:10439-10447.

    Not in our library10.1074/jbc.m512305200

21. 21.

    Arnaiz-Villena A, Morales P, Gomez-Casado E, Castro MJ, Varela P, Rojo-Amigo R, Martinez-Laso J. Evolution of MHC-G in primates: A different kind of molecule for each group of species. J. Reprod. Immunol. 1999;43:111-125.

    Not in our library10.1016/s0165-0378(99)00026-1

22. 22.

    Allen RL, O'Callaghan CA, McMichael AJ, Bowness P. Cutting Edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. J. Immunol. 1999;162:5045-5048.

    Not in our library

23. 23.

    Hutter H, Hammer A, Blaschitz A, Hartmann M, Ebbesen P, Dohr G, Ziegler A, Uchanska-Ziegler B. Expression of HLA class I molecules in human first trimester and term placenta trophoblast. Cell Tissue Res. 1996;286:439-447.

    Not in our library10.1007/s004410050713

24. 24.

    King A, Burrows TD, Hiby SE, Bowen JM, Joseph S, Verma S, Lim PB, et al. Surface expression of HLA-C antigen by human extravillous trophoblast. Placenta. 2000;21:376-387.

    Not in our library10.1053/plac.1999.0496

25. 25.

    Trundley A, Gardner L, Northfield J, Chang C, Moffett A. Methods for isolation of cells from the human fetal-maternal interface. Methods Mol. Med. 2006;122:109-122.

    Not in our library10.1385/1-59259-989-3:109

26. 26.

    Dong Y, Lieskovska J, Kedrin D, Porcelli S, Mandelboim O, Bushkin Y. Soluble nonclassical HLA generated by the metalloproteinase pathway. Hum. Immunol. 2003;64:802-810.

    Not in our library10.1016/s0198-8859(03)00093-4

27. 27.

    Park GM, Lee S, Park B, Kim E, Shin J, Cho K, Ahn K. Soluble HLA-G generated by proteolytic shedding inhibits NK-mediated cell lysis. Biochem. Biophys. Res. Commun. 2004;313:606-611.

    Not in our library10.1016/j.bbrc.2003.11.153

28. 28.

    Fujii T, Ishitani A, Geraghty DE. A soluble form of the HLA-G antigen is encoded by a messenger ribonucleic acid containing intron 4. J. Immunol. 1994;153:5516-5524.

    Not in our library

29. 29.

    Springer TA, Robb RJ, Terhorst C, Strominger JL. Subunit and disulfide structure of monomeric and dimeric forms of detergent-soluble HLA antigens. J. Biol. Chem. 1977;252:4694-4700.

    Not in our library

30. 30.

    Bird LA, Peh CA, Kollnberger S, Elliott T, McMichael AJ, Bowness P. Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling. Eur. J. Immunol. 2003;33:748-759.

    Not in our library10.1002/eji.200323678

31. 31.

    Chang CC, Murphy SP, Ferrone S. Differential in vivo and in vitro HLA-G expression in melanoma cells: Potential mechanisms. Hum. Immunol. 2003;64:1057-1063.

    Not in our library10.1016/j.humimm.2003.08.357

32. 32.

    Gardner L, Moffett A. Dendritic cells in the human decidua. Biol. Reprod. 2003;69:1438-1446.

    Not in our library10.1095/biolreprod.103.017574

33. 33.

    Borges L, Hsu ML, Fanger N, Kubin M, Cosman D. A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules. J. Immunol. 1997;159:5192-5196.

    Not in our library

34. 34.

    Bainbridge DR, Ellis SA, Sargent IL. HLA-G suppresses proliferation of CD4(+) T-lymphocytes. J. Reprod. Immunol. 2000;48:17-26.

    Not in our library10.1016/s0165-0378(00)00070-x

35. 35.

    Riteau B, Menier C, Khalil-Daher I, Sedlik C, Dausset J, Rouas-Freiss N, Carosella ED. HLA-G inhibits the allogeneic proliferative response. J. Reprod. Immunol. 1999;43:203-211.

    Not in our library10.1016/s0165-0378(99)00034-0

36. 36.

    van der Meer A, Lukassen HG, van Lierop MJ, Wijnands F, Mosselman S, Braat DD, Joosten I. Membrane-bound HLA-G activates proliferation and interferon-gamma production by uterine natural killer cells. Mol. Hum. Reprod. 2004;10:189-195.

    Not in our library10.1093/molehr/gah032

37. 37.

    Colonna M, Navarro F, Bellon T, Llano M, Garcia P, Samaridis J, Angman L, et al. A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J. Exp. Med. 1997;186:1809-1818.

    Not in our library10.1084/jem.186.11.1809

38. 38.

    Allan DS, Colonna M, Lanier LL, Churakova TD, Abrams JS, Ellis SA, McMichael AJ, Braud VM. Tetrameric complexes of human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells. J. Exp. Med. 1999;189:1149-1156.

    Not in our library10.1084/jem.189.7.1149

39. 39.

    Petroff MG, Sedlmayr P, Azzola D, Hunt JS. Decidual macrophages are potentially susceptible to inhibition by class Ia and class Ib HLA molecules. J. Reprod. Immunol. 2002;56:3-17.

    Not in our library10.1016/s0165-0378(02)00024-4

40. 40.

    Fanger NA, Cosman D, Peterson L, Braddy SC, Maliszewski CR, Borges L. The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes. Eur. J. Immunol. 1998;28:3423-3434.

    Not in our library10.1002/(sici)1521-4141(199811)28:11<3423::aid-immu3423>3.0.co;2-2

41. 41.

    Le Friec G, Laupeze B, Fardel O, Sebti Y, Pangault C, Guilloux V, Beauplet A, et al. Soluble HLA-G inhibits human dendritic cell-triggered allogeneic T-cell proliferation without altering dendritic differentiation and maturation processes. Hum. Immunol. 2003;64:752-761.

    Not in our library10.1016/s0198-8859(03)00091-0

42. 42.

    Ristich V, Liang S, Zhang W, Wu J, Horuzsko A. Tolerization of dendritic cells by HLA-G. Eur. J. Immunol. 2005;35:1133-1142.

    Not in our library10.1002/eji.200425741

43. 43.

    Buelens C, Verhasselt V, De Groote D, Thielemans K, Goldman M, Willems F. Interleukin-10 prevents the generation of dendritic cells from human peripheral blood mononuclear cells cultured with interleukin-4 and granulocyte/macrophage-colony-stimulating factor. Eur. J. Immunol. 1997;27:756-762.

    Not in our library10.1002/eji.1830270326

44. 44.

    Gurney KB, Elliott J, Nassanian H, Song C, Soilleux E, McGowan I, Anton PA, Lee B. Binding and transfer of human immunodeficiency virus by DC-SIGN+ cells in human rectal mucosa. J. Virol. 2005;79:5762-5773.

    Not in our library10.1128/jvi.79.9.5762-5773.2005

45. 45.

    Reis e Sousa C. Dendritic cells in a mature age. Nat. Rev. Immunol. 2006;6:476-483.

    Not in our library10.1038/nri1845

46. 46.

    Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells: Which signals induce tolerance or immunity? Trends Immunol. 2002;23:445-449.

    Not in our library10.1016/s1471-4906(02)02281-0

47. 47.

    Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 2001;19:683-765.

    Not in our library10.1146/annurev.immunol.19.1.683

48. 48.

    Hegde S, Pahne J, Smola-Hess S. Novel immunosuppressive properties of interleukin-6 in dendritic cells: Inhibition of NF-kappaB binding activity and CCR7 expression. FASEB J. 2004;18:1439-1441.

    Not in our library10.1096/fj.03-0969fje

49. 49.

    Rimoldi M, Chieppa M, Salucci V, Avogadri F, Sonzogni A, Sampietro GM, Nespoli A, et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat. Immunol. 2005;6:507-514.

    Not in our library10.1038/ni1192

50. 50.

    McIntire RH, Morales PJ, Petroff MG, Colonna M, Hunt JS. Recombinant HLA-G5 and -G6 drive U937 myelomonocytic cell production of TGF-beta1. J. Leukoc. Biol. 2004;76:1220-1228.

    Not in our library10.1189/jlb.0604337

51. 51.

    Beinhauer BG, McBride JM, Graf P, Pursch E, Bongers M, Rogy M, Korthauer U, et al. Interleukin 10 regulates cell surface and soluble LIR-2 (CD85d) expression on dendritic cells resulting in T cell hyporesponsiveness in vitro. Eur. J. Immunol. 2004;34:74-80.

    Not in our library10.1002/eji.200324550

52. 52.

    Tenca C, Merlo A, Merck E, Bates EE, Saverino D, Simone R, Zarcone D, et al. CD85j (leukocyte Ig-like receptor-1/Ig-like transcript 2) inhibits human osteoclast-associated receptor-mediated activation of human dendritic cells. J. Immunol. 2005;174:6757-6763.

    Not in our library10.4049/jimmunol.174.11.6757

53. 53.

    Chang CC, Ciubotariu R, Manavalan JS, Yuan J, Colovai AI, Piazza F, Lederman S, et al. Tolerization of dendritic cells by T(S) cells: The crucial role of inhibitory receptors ILT3 and ILT4. Nat. Immunol. 2002;3:237-243.

    Not in our library10.1038/ni760

54. 54.

    Watanabe N, Wang YH, Lee HK, Ito T, Wang YH, Cao W, Liu YJ. Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature. 2005;436:1181-1185.

    Not in our library10.1038/nature03886

55. 55.

    Gonzalez-Rey E, Chorny A, Fernandez-Martin A, Ganea D, Delgado M. Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells. Blood. 2006;107:3632-3638.

    Not in our library10.1182/blood-2005-11-4497

56. 56.

    Moretta A. Natural killer cells and dendritic cells: Rendezvous in abused tissues. Nat. Rev. Immunol. 2002;2:957-964.

    Not in our library10.1038/nri956

57. 57.

    Moffett A, Loke C. Immunology of placentation in eutherian mammals. Nat. Rev. Immunol. 2006;6:584-594.

    Not in our library10.1038/nri1897

58. 58.

    Shimizu Y, DeMars R. Production of human cells expressing individual transferred HLA-A,-B,-C genes using an HLA-A,-B,-C null human cell line. J. Immunol. 1989;142:3320-3328.

    Not in our library

59. 59.

    Chumbley G, King A, Gardner L, Howlett S, Holmes N, Loke YW. Generation of an antibody to HLA-G in transgenic mice and demonstration of the tissue reactivity of this antibody. J. Reprod. Immunol. 1994;27:173-186.

    Not in our library10.1016/0165-0378(94)90002-7

60. 60.

    Lee N, Malacko AR, Ishitani A, Chen MC, Bajorath J, Marquardt H, Geraghty DE. The membrane-bound and soluble forms of HLA-G bind identical sets of endogenous peptides but differ with respect to TAP association. Immunity. 1995;3:591-600.

    Not in our library10.1016/1074-7613(95)90130-2

61. 61.

    Menier C, Saez B, Horejsi V, Martinozzi S, Krawice-Radanne I, Bruel S, Le Danff C, et al. Characterization of monoclonal antibodies recognizing HLA-G or HLA-E: New tools to analyze the expression of nonclassical HLA class I molecules. Hum. Immunol. 2003;64:315-326.

    Not in our library10.1016/s0198-8859(02)00821-2

62. 62.

    Brodsky FM, Bodmer WF, Parham P. Characterization of a monoclonal anti-beta 2-microglobulin antibody and its use in the genetic and biochemical analysis of major histocompatibility antigens. Eur. J. Immunol. 1979;9:536-545.

    Not in our library10.1002/eji.1830090709

63. 63.

    Parham P, Barnstable CJ, Bodmer WF. Use of a monoclonal antibody (W6/32) in structural studies of HLA-A,B,C antigens. J. Immunol. 1979;123:342-349.

    Not in our library

64. 64.

    Rebai N, Malissen B. Structural and genetic analyses of HLA class I molecules using monoclonal xenoantibodies. Tissue Antigens. 1983;22:107-117.

    Not in our library10.1111/j.1399-0039.1983.tb01176.x

65. 65.

    Hurks HM, Valter MM, Wilson L, Hilgert I, van den Elsen PJ, Jager MJ. Uveal melanoma: No expression of HLA-G. Invest. Ophthalmol. Vis. Sci. 2001;42:3081-3084.

    Not in our library

66. 66.

    Cosman D, Fanger N, Borges L, Kubin M, Chin W, Peterson L, Hsu ML. A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity. 1997;7:273-282.

    Not in our library10.1016/s1074-7613(00)80529-4

67. 67.

    Colonna M, Samaridis J, Cella M, Angman L, Allen RL, O'Callaghan CA, Dunbar R, et al. Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J. Immunol. 1998;160:3096-3100.

    Not in our library

68. 68.

    Parham P. On the fragmentation of monoclonal IgG1, IgG2a, and IgG2b from BALB/c mice. J. Immunol. 1983;131:2895-2902.

    Not in our library

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