1887

Journal of General Virology

Volume 84, Issue 2

Induction of HLA-G-restricted human cytomegalovirus pp65 (UL83)-specific cytotoxic T lymphocytes in HLA-G transgenic mice Free

Abstract

The non-classical major histocompatibility complex class I molecule HLA-G is expressed mainly by extravillous trophoblasts at the materno–foetal interface. HLA-G has been found to bind endogenously processed nonameric peptides but its function as a restriction element for a cytotoxic T cell response to viruses with tropism for trophoblastic cells has never been demonstrated. In this study, candidate viral peptides derived from human cytomegalovirus (HCMV) pp65 (UL83), which stabilized the HLA-G molecule on HLA-G-transfected T2 cells, were identified. The specific anti-pp65 cytotoxic T lymphocyte (CTL) response restricted by HLA-G in triple transgenic mice (HLA-G, human β2m, human CD8α) was then investigated by injection of dendritic cells loaded with synthetic pp65-derived peptides or by infection with canarypox virus expressing pp65. Results showed that CTLs from HLA-G mice have the capacity to kill target cells either infected with recombinant vaccinia viruses expressing pp65 or loaded with specific pp65-derived peptides using HLA-G as an antigen-presenting molecule. It was also demonstrated that these HLA-G-restricted pp65-specific T cells are able to kill the human astrocytoma cell line U373, which was transfected with HLA-G and infected with HCMV. Moreover, using HLA-G tetramers refolded with a synthetic pp65-derived peptide, peptide-specific CD8 cells restricted by HLA-G have been detected . These findings provide the first evidence that HLA-G can select anti-HCMV-restricted CTLs , although the potency of this cytolytic response is limited (20–25 %). The weak HLA-G-restricted anti-HCMV response is probably due to HLA-G-mediated inhibitory signals on the development of an antiviral CTL response.

  • Received:
  • Accepted:
  • Published Online:
SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.18735-0
2003-02-01
2020-06-06
Loading full text...

Full text loading...

/deliver/fulltext/jgv/84/2/vir840307.html?itemId=/content/journal/jgv/10.1099/vir.0.18735-0&mimeType=html&fmt=ahah

References

  1. Allan D. S., Colonna M., Lanier L. L., Churakova T. D., Abrams J. S., Ellis S. A., McMichael A. J., Braud V. M.. 1999; Tetrameric complexes of human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells. J Exp Med189:1149–1156
     [Google Scholar]
  2. Arrode G., Boccaccio C., Lule J., Allart S., Moinard N., Abastado J. P., Alam A., Davrinche C.. 2000; Incoming human cytomegalovirus pp65 (UL83) contained in apoptotic infected fibroblasts is cross-presented to CD8+ T cells by dendritic cells. J Virol74:10018–10024
     [Google Scholar]
  3. Blaschitz A., Lenfant F., Mallet V., Hartmann M., Bensussan A., Geraghty D. E., Le Bouteiller P., Dohr G.. 1997; Endothelial cells in chorionic fetal vessels of first trimester placenta express HLA-G. Eur J Immunol27:3380–3388
     [Google Scholar]
  4. Braud V. M., McMichael A. J.. 1999; Regulation of NK cell functions through interaction of the CD94/NKG2 receptors with the nonclassical class I molecule HLA-E. Curr Top Microbiol Immunol244:85–95
     [Google Scholar]
  5. Braud V. M., Allan D. S., Wilson D., McMichael A. J.. 1998; TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide. Curr Biol8:1–10
     [Google Scholar]
  6. Clover L. M., Sargent I. L., Townsend A., Tampe R., Redman C. W.. 1995; Expression of TAP1 by human trophoblast. Eur J Immunol25:543–553
     [Google Scholar]
  7. Crisa L., McMaster M. T., Ishii J. K., Fisher S. J., Salomon D. R.. 1997; Identification of a thymic epithelial cell subset sharing expression of the class Ib HLA-G molecule with fetal trophoblasts. J Exp Med186:289–298
     [Google Scholar]
  8. DeMars R., Chang C. C., Shaw S., Reitnauer P. J., Sondel P. M.. 1984; Homozygous deletions that simultaneously eliminate expressions of class I and class II antigens of EBV-transformed B-lymphoblastoid cells. I. Reduced proliferative responses of autologous and allogeneic T cells to mutant cells that have decreased expression of class II antigens. Hum Immunol11:77–97
     [Google Scholar]
  9. Diehl M., Munz C., Keilholz W., Stevanovic S., Holmes N., Loke Y. W., Rammensee H. G.. 1996; Nonclassical HLA-G molecules are classical peptide presenters. Curr Biol6:305–314
     [Google Scholar]
  10. Duclos H., Elfassi E., Michelson S., Arenzana-Seisdedos F., Hazan U., Munier A., Virelizier J. L.. 1989; Cytomegalovirus infection and trans-activation of HIV-1 and HIV-2 LTRs in human astrocytoma cells. AIDS Res Hum Retroviruses5:217–224
     [Google Scholar]
  11. Fisher S., Genbacev O., Maidji E., Pereira L.. 2000; Human cytomegalovirus infection of placental cytotrophoblasts in vitro and in utero : implications for transmission and pathogenesis. J Virol74:6808–6820
     [Google Scholar]
  12. Fournel S., Aguerre-Girr M., Huc X., Lenfant F., Alam A., Toubert A., Bensussan A., Le Bouteiller P.. 2000; Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8. J Immunol164:6100–6104
     [Google Scholar]
  13. Fowler D. H., Breglio J., Nagel G., Eckhaus M. A., Gress R. E.. 1996; Allospecific CD8+ Tc1 and Tc2 populations in graft-versus-leukemia effect and graft-versus-host disease. J Immunol157:4811–4821
     [Google Scholar]
  14. Fox H.. 1993; The placenta and infection. In The Human Placenta pp 313–333 Edited by Redman C. W., Sargent I. L., Starkey P. M.. Oxford: Blackwell Science;
     [Google Scholar]
  15. Gobin S. J., Wilson L., Keijsers V., Van den Elsen P. J.. 1997; Antigen processing and presentation by human trophoblast-derived cell lines. J Immunol158:3587–3592
     [Google Scholar]
  16. Gonczol E., Berensci K., Pincus S., Endresz V., Meric C., Paoletti E., Plotkin S. A.. 1995; Preclinical evaluation of an ALVAC (canarypox): human cytomegalovirus glycoprotein B vaccine candidate. Vaccine13:1080–1085
     [Google Scholar]
  17. Hemmings D. G., Kilani R., Nykiforuk C., Preiksaitis J., Guilbert L. J.. 1998; Permissive cytomegalovirus infection of primary villous term and first trimester trophoblasts. J Virol72:4970–4979
     [Google Scholar]
  18. Horuzsko A., Antoniou J., Tomlinson P., Portik-Dobos V., Mellor A. L.. 1997; HLA-G functions as a restriction element and a transplantation antigen in mice. Int Immunol9:645–653
     [Google Scholar]
  19. Horuzsko A., Portik-Dobos V., Hansen K. A., Markowitz R. B., Helman S. W., Mellor A. L.. 1999; Induction of HLA-G-specific human CD8+ T cell lines by stimulation across a polymorphism of HLA-G. Transplant Proc31:1860–1863
     [Google Scholar]
  20. Horuzsko A., Lenfant F., Munn D. H., Mellor A. L.. 2001; Maturation of antigen-presenting cells is compromised in HLA-G transgenic mice. Int Immunol13:385–394
     [Google Scholar]
  21. Inaba K., Inaba M., Romani N., Aya H., Deguchi M., Ikehara S., Muramatsu S., Steinman R. M.. 1992; Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med176:1693–1702
     [Google Scholar]
  22. Ishitani A., Geraghty D. E.. 1992; Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens. Proc Natl Acad Sci U S A89:3947–3951
     [Google Scholar]
  23. Kern F., Surel I. P., Faulhaber N., Frommel C., Schneider-Mergener J., Schonemann C., Reinke P., Volk H. D.. 1999; Target structures of the CD8+-T-cell response to human cytomegalovirus: the 72-kilodalton major immediate-early protein revisited. J Virol73:8179–8184
     [Google Scholar]
  24. King A., Allan D. S., Bowen M., Powis S. J., Joseph S., Verma S., Hiby S. E., McMichael A. J., Loke Y. W., Braud V. M.. 2000; HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells. Eur J Immunol30:1623–1631
     [Google Scholar]
  25. Kovats S., Main E. K., Librach C., Stubblebine M., Fisher S. J., DeMars R.. 1990; A class I antigen, HLA-G, expressed in human trophoblasts. Science248:220–223
     [Google Scholar]
  26. Kriel R. L., Gates G. A., Wulff H., Powell N., Poland J. D., Chin T. D.. 1970; Cytomegalovirus isolations associated with pregnancy wastage. Am J Obstet Gynecol106:885–892
     [Google Scholar]
  27. Lanier L. L.. 1999; Natural killer cells fertile with receptors for HLA-G?. Proc Natl Acad Sci U S A96:5343–5345
     [Google Scholar]
  28. Le Bouteiller P., Solier C., Proll J., Aguerre-Girr M., Fournel S., Lenfant F.. 1999; Placental HLA-G protein expression in vivo : where and what for?. Hum Reprod Update5:223–233
     [Google Scholar]
  29. Lee N., Malacko A. R., Ishitani A., Chen M. C., Bajorath J., Marquardt H., Geraghty D. E.. 1995; The membrane-bound and soluble forms of HLA-G bind identical sets of endogenous peptides but differ with respect to TAP association. Immunity3:591–600
     [Google Scholar]
  30. Lee N., Goodlett D. R., Ishitani A., Marquardt H., Geraghty D. E.. 1998; HLA-E surface expression depends on binding of TAP-dependent peptides derived from certain HLA class I signal sequences. J Immunol160:4951–4960
     [Google Scholar]
  31. Le Gal F. A., Riteau B., Sedlik C., Khalil-Daher I., Menier C., Dausset J., Guillet J. G., Carosella E. D., Rouas-Freiss N.. 1999; HLA-G-mediated inhibition of antigen-specific cytotoxic T lymphocytes. Int Immunol11:1351–1356
     [Google Scholar]
  32. Lew J. F., Fowler M. G.. 1998; Perinatal HIV-1 transmission in the United States and Internationally. Trophoblast Res12:85–103
     [Google Scholar]
  33. Liang S., Baibakov B., Horuzsko A.. 2002; HLA-G inhibits the functions of murine dendritic cells via the PIR-B immune inhibitory receptor. Eur J Immunol32:2418–2426
     [Google Scholar]
  34. Lozano J. M., Gonzalez R., Kindelan J. M., Rouas-Freiss N., Caballos R., Dausset J., Carosella E. D., Pena J.. 2002; Monocytes and T lymphocytes in HIV-1-positive patients express HLA-G molecule. AIDS16:347–351
     [Google Scholar]
  35. Ludewig B., Ehl S., Karrer U., Odermatt B., Hengartner H., Zinkernagel R. M.. 1998; Dendritic cells efficiently induce protective antiviral immunity. J Virol72:3812–3818
     [Google Scholar]
  36. Mallet V., Blaschitz A., Crisa L., Schmitt C., Fournel S., King A., Loke Y. W., Dohr G., Le Bouteiller P.. 1999; HLA-G in the human thymus: a subpopulation of medullary epithelial but not CD83+ dendritic cells expresses HLA-G as a membrane-bound and soluble protein. Int Immunol11:889–898
     [Google Scholar]
  37. McLaughlin-Taylor E., Pande H., Forman S. J., Tanamachi B., Li C.R., Zaia J. A., Greenberg P. D., Riddell S. R.. 1994; Identification of the major late human cytomegalovirus matrix protein pp65 as a target antigen for CD8+ virus-specific cytotoxic T lymphocytes. J Med Virol43:103–110
     [Google Scholar]
  38. Moris A., Teichgraber V., Gauthier L., Buhring H. J., Rammensee H. G.. 2001; Cutting edge: characterization of allorestricted and peptide-selective alloreactive T cells using HLA-tetramer selection. J Immunol166:4818–4821
     [Google Scholar]
  39. Naib Z. M., Nahmias A. J., Josey W. E., Wheeler J. H.. 1970; Association of maternal genital herpetic infection with spontaneous abortion. Obstet Gynecol35:260–263
     [Google Scholar]
  40. Onno M., Le Friec G., Pangault C., Amiot L., Guilloux V., Drenou B., Caulet-Maugendre S., Andre P., Fauchet R.. 2000; Modulation of HLA-G antigens expression in myelomonocytic cells. Hum Immunol61:1086–1094
     [Google Scholar]
  41. Park B., Lee S., Kim E., Chang S., Jin M., Ahn K.. 2001; The truncated cytoplasmic tail of HLA-G serves a quality-control function in post-ER compartments. Immunity15:213–224
     [Google Scholar]
  42. Plotkin S. A.. 1994; Vaccines for varicella-zoster virus and cytomegalovirus: recent progress. Science265:1383–1385
     [Google Scholar]
  43. Salter R. D., Cresswell P.. 1986; Impaired assembly and transport of HLA-A and -B antigens in a mutant TxB cell hybrid. EMBO J5:943–949
     [Google Scholar]
  44. Sanders S. K., Giblin P. A., Kavathas P.. 1991; Cell–cell adhesion mediated by CD8 and human histocompatibility leukocyte antigen G, a nonclassical major histocompatibility complex class 1 molecule on cytotrophoblasts. J Exp Med174:737–740
     [Google Scholar]
  45. Schmidt C. M., Garrett E., Orr H. T.. 1997; Cytotoxic T lymphocyte recognition of HLA-G in mice. Hum Immunol55:127–139
     [Google Scholar]
  46. Solache A., Morgan C. L., Dodi A. I., Morte C., Scott I., Baboonian C., Zal B., Goldman J., Grundy J. E., Madrigal J. A.. 1999; Identification of three HLA-A*0201-restricted cytotoxic T cell epitopes in the cytomegalovirus protein pp65 that are conserved between eight strains of the virus. J Immunol163:5512–5518
     [Google Scholar]
  47. Spencer J. V., Lockridge K. M., Barry P. A., Lin G., Tsang M., Penfold M. E., Schall T. J.. 2002; Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10. J Virol76:1285–1292
     [Google Scholar]
  48. Vaz-Santiago J., Lule J., Rohrlich P., Jacquier C., Gibert N., Le Roy E., Betbeder D., Davignon J. L., Davrinche C.. 2001; Ex vivo stimulation and expansion of both CD4+ and CD8+ T cells from peripheral blood mononuclear cells of human cytomegalovirus-seropositive blood donors by using a soluble recombinant chimeric protein, IE1–pp65. J Virol75:7840–7847
     [Google Scholar]
  49. Walter E. A., Greenberg P. D., Gilbert M. J., Finch R. J., Watanabe K. S., Thomas E. D., Riddell S. R.. 1995; Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med333:1038–1044
     [Google Scholar]
  50. Wills M. R., Carmichael A. J., Mynard K., Jin X., Weekes M. P., Plachter B., Sissons J. G.. 1996; The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T- cell receptor usage of pp65-specific CTL. J Virol70:7569–7579
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.18735-0
Loading
Induction of HLA-G-restricted human cytomegalovirus pp65 (UL83)-specific cytotoxic T lymphocytes in HLA-G transgenic mice
J. Gen. Virol. 84, 307 (2003); https://doi.org/10.1099/vir.0.18735-0
/content/journal/jgv/10.1099/vir.0.18735-0
/content/journal/jgv/10.1099/vir.0.18735-0
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error