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PMID: 19155503 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Cytomegalovirus-infected human endothelial cells can stimulate allogeneic CD4+ memory T cells by releasing antigenic exosomes.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 182 ·No. 3 ·2009-02-01 ·Pages 1548-59

Walker JD, Maier CL, Pober JS

Abstract

Human CMV infection is controlled by T cell-mediated immunity and in immunosuppressed transplant patients it is associated with acute allograft rejection as well as chronic allograft vasculopathy. CMV infects endothelial cells (EC) and it is thought that CMV-specific host immune responses to infected allograft EC contribute to rejection. In vitro, CD4(+) T cells from CMV-positive donors (but not CMV-negative donors) are readily activated by CMV-infected allogeneic EC, although it is unclear how allogeneic CMV-infected EC activate self-class II MHC-restricted memory CD4(+) T cells. In this study, we confirm that purified CD4(+) T cells from CMV(+) donors are activated by allogeneic CMV-infected EC, but find that the response is dependent upon copurified APC expressing class II MHC that are autologous to the T cells. The transfer of CMV Ags from infected EC to APC can be mediated by EC-derived exosome-like particles. These results provide a mechanism by which CMV can exacerbate allograft rejection and suggest a novel function of EC-derived exosomes that could contribute in a more general manner to immune surveillance.

MeSH Terms
Antigens, Viral/physiology CD4-Positive T-Lymphocytes/immunology,metabolism,virology Cells, Cultured Coculture Techniques Culture Media, Conditioned Cytomegalovirus/immunology Endothelium, Vascular/immunology,metabolism,pathology,virology Exosomes/immunology,metabolism,virology HLA-DR Antigens/biosynthesis,genetics Humans Immunologic Memory/genetics Lymphocyte Activation/immunology Transplantation Immunology/genetics Transplantation, Homologous
Chemicals
Antigens, Viral Culture Media, Conditioned HLA-DR Antigens
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Walker Jason D
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Maier Cheryl L
Pober Jordan S
References (73)
73 references, click to expand
  1. Clonal analysis of human cytotoxic T lymphocytes: T4+ and T8+ effector T cells recognize products of different major histocompatibility complex regions.
    Proc Natl Acad Sci U S A. 1982 Jul;79(14):4395-9 PMID: 6981813
  2. Exosomal-like vesicles are present in human blood plasma.
    Int Immunol. 2005 Jul;17(7):879-87 PMID: 15908444
  3. Late-acute renal allograft rejection and symptomless cytomegalovirus infection.
    Lancet. 1994 Dec 24-31;344(8939-8940):1737-8 PMID: 7741857
  4. Risk factors for chronic rejection in renal allograft recipients.
    Transplantation. 1993 Apr;55(4):752-6; discussion 756-7 PMID: 8475548
  5. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles.
    J Immunol. 2001 Jun 15;166(12):7309-18 PMID: 11390481
  6. Human cytomegalovirus penetrates host cells by pH-independent fusion at the cell surface.
    Virology. 1992 Nov;191(1):387-95 PMID: 1329327
  7. Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon.
    J Exp Med. 1983 Apr 1;157(4):1339-53 PMID: 6403654
  8. The cathepsin B death pathway contributes to TNF plus IFN-gamma-mediated human endothelial injury.
    J Immunol. 2005 Aug 1;175(3):1858-66 PMID: 16034129
  9. Prolonged cytomegalovirus infection with viremia is associated with development of cardiac allograft vasculopathy.
    J Heart Lung Transplant. 1992 May-Jun;11(3 Pt 2):S133-7 PMID: 1320405
  10. Widespread presence of histologically occult cytomegalovirus.
    Hum Pathol. 1984 May;15(5):430-9 PMID: 6327494
  11. Exosomes: composition, biogenesis and function.
    Nat Rev Immunol. 2002 Aug;2(8):569-79 PMID: 12154376
  12. Cytomegalovirus- and interferon-related effects on human endothelial cells. Cytomegalovirus infection reduces upregulation of HLA class II antigen expression after treatment with interferon-gamma.
    Hum Immunol. 1992 Dec;35(4):230-8 PMID: 1284062
  13. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease.
    Blood. 2003 Apr 1;101(7):2686-92 PMID: 12411292
  14. Human CD4+ T cells proliferate to HLA-DR+ allogeneic vascular endothelium. Identification of accessory interactions.
    Transplantation. 1993 Jul;56(1):128-34 PMID: 7687392
  15. Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction.
    Blood. 2008 Jan 1;111(1):175-82 PMID: 17895402
  16. In vitro induction of endothelial HLA class II antigen expression by cytomegalovirus-activated CD4+ T cells.
    Transplantation. 1993 Dec;56(6):1504-12 PMID: 7904091
  17. Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: a post hoc analysis of a randomized, placebo-controlled study.
    Circulation. 1999 Jul 6;100(1):61-6 PMID: 10393682
  18. Interferon-gamma elicits arteriosclerosis in the absence of leukocytes.
    Nature. 2000 Jan 13;403(6766):207-11 PMID: 10646607
  19. Long-term stable expanded human CD4+ T cell clones specific for human cytomegalovirus are distributed in both CD45RAhigh and CD45ROhigh populations.
    J Immunol. 2004 Nov 1;173(9):5843-51 PMID: 15494538
  20. CMV as an exacerbating agent in transplant vascular sclerosis: potential immune-mediated mechanisms modelled in vitro.
    Transplant Proc. 1997 Feb-Mar;29(1-2):1545-6 PMID: 9123420
  21. Can graft endothelial cells initiate a host anti-graft immune response?
    Transplantation. 1996 Feb 15;61(3):343-9 PMID: 8610337
  22. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells.
    Blood. 2004 Nov 15;104(10):3257-66 PMID: 15284116
  23. The dominant phosphoprotein pp65 (UL83) of human cytomegalovirus is dispensable for growth in cell culture.
    J Virol. 1995 Oct;69(10):5959-68 PMID: 7666500
  24. T lymphocyte activation by staphylococcal enterotoxins: role of class II molecules and T cell surface structures.
    Cell Immunol. 1989 Apr 15;120(1):92-101 PMID: 2522832
  25. T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells.
    Gastroenterology. 2007 May;132(5):1866-76 PMID: 17484880
  26. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant.
    J Clin Invest. 1999 Jul;104(1):93-102 PMID: 10393703
  27. Replication of human cytomegalovirus in endothelial cells.
    J Infect Dis. 1984 Dec;150(6):956-7 PMID: 6094680
  28. Antigen presentation by interferon-gamma-treated endothelial cells and fibroblasts: differential ability to function as antigen-presenting cells despite comparable Ia expression.
    J Immunol. 1985 Dec;135(6):3750-62 PMID: 3934267
  29. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles.
    Biochim Biophys Acta. 1981 Jul 6;645(1):63-70 PMID: 6266476
  30. Endogenous human cytomegalovirus gB is presented efficiently by MHC class II molecules to CD4+ CTL.
    J Exp Med. 2005 Oct 17;202(8):1109-19 PMID: 16216889
  31. Localization of HCMV UL33 and US27 in endocytic compartments and viral membranes.
    Traffic. 2002 Mar;3(3):218-32 PMID: 11886592
  32. Propagation and purification of high-titer human cytomegalovirus.
    Appl Microbiol. 1971 Nov;22(5):914-8 PMID: 4332045
  33. Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo.
    Blood. 2007 Nov 1;110(9):3234-44 PMID: 17666571
  34. Cytomegalovirus in solid organ transplantation.
    Transpl Infect Dis. 2001;3 Suppl 2:1-5 PMID: 11926743
  35. Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway.
    J Exp Med. 1998 Mar 2;187(5):675-83 PMID: 9480977
  36. Isolation and characterization of exosomes from cell culture supernatants and biological fluids.
    Curr Protoc Cell Biol. 2006 Apr;Chapter 3:Unit 3.22 PMID: 18228490
  37. Cytomegalovirus inhibits major histocompatibility class II expression on infected endothelial cells.
    Am J Pathol. 1994 Apr;144(4):683-92 PMID: 8160770
  38. Glycoprotein B of human cytomegalovirus promotes virion penetration into cells, transmission of infection from cell to cell, and fusion of infected cells.
    Virology. 1993 Nov;197(1):143-58 PMID: 7692667
  39. Human vascular endothelial cells process and present autoantigen to human T cell lines.
    Int Immunol. 1995 Mar;7(3):471-9 PMID: 7540863
  40. High T-cell response to human cytomegalovirus induces chemokine-mediated endothelial cell damage.
    Blood. 2007 Sep 15;110(6):1857-63 PMID: 17519388
  41. CMV infection, class II antigen expression, and human kidney allograft rejection.
    Transplantation. 1986 Oct;42(4):364-7 PMID: 3020747
  42. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system.
    Nature. 1974 Apr 19;248(5450):701-2 PMID: 4133807
  43. Cellular immunity and active human cytomegalovirus infection in patients with septic shock.
    J Infect Dis. 2007 Nov 1;196(9):1288-95 PMID: 17922392
  44. Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells.
    Nat Med. 1999 Sep;5(9):1039-43 PMID: 10470081
  45. Enhanced endothelial cytopathogenicity induced by a cytomegalovirus strain propagated in endothelial cells.
    J Med Virol. 1989 Aug;28(4):223-30 PMID: 2550582
  46. Antigen-presenting function of human endothelial cells. Direct activation of resting CD8 T cells.
    J Immunol. 1994 Dec 15;153(12):5402-12 PMID: 7989746
  47. Modification of human cytomegalovirus tropism through propagation in vitro is associated with changes in the viral genome.
    J Gen Virol. 1999 Nov;80 ( Pt 11):2867-2877 PMID: 10580048
  48. Accumulation of virion tegument and envelope proteins in a stable cytoplasmic compartment during human cytomegalovirus replication: characterization of a potential site of virus assembly.
    J Virol. 2000 Jan;74(2):975-86 PMID: 10623760
  49. Nuclear targeting of the tegument protein pp65 (UL83) of human cytomegalovirus: an unusual bipartite nuclear localization signal functions with other portions of the protein to mediate its efficient nuclear transport.
    J Virol. 1995 Feb;69(2):1071-8 PMID: 7815485
  50. Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon.
    J Immunol. 1986 Sep 15;137(6):1893-6 PMID: 3091693
  51. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes.
    J Cell Biol. 1985 Sep;101(3):942-8 PMID: 2993317
  52. Identification of proteins in human cytomegalovirus (HCMV) particles: the HCMV proteome.
    J Virol. 2004 Oct;78(20):10960-6 PMID: 15452216
  53. The morphogenesis of human cytomegalovirus. Isolation and polypeptide characterization of cytomegalovirions and dense bodies.
    Virology. 1975 Aug;66(2):464-73 PMID: 168685
  54. An in vitro model of T cell activation by autologous cytomegalovirus (CMV)-infected human adult endothelial cells: contribution of CMV-enhanced endothelial ICAM-1.
    J Immunol. 1998 Apr 1;160(7):3143-51 PMID: 9531269
  55. Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses.
    Blood Cells Mol Dis. 2005 Sep-Oct;35(2):89-93 PMID: 15990342
  56. Lymphocytes recognize human vascular endothelial and dermal fibroblast Ia antigens induced by recombinant immune interferon.
    Nature. 1983 Oct 20-26;305(5936):726-9 PMID: 6415484
  57. Identification of the human cytomegalovirus glycoprotein B gene and induction of neutralizing antibodies via its expression in recombinant vaccinia virus.
    EMBO J. 1986 Nov;5(11):3057-63 PMID: 3024973
  58. Endothelial HLA class II induction mediated by allogeneic T cells activated by cytomegalovirus-infected cultured endothelial cells.
    Transplant Proc. 1993 Feb;25(1 Pt 2):1439-40 PMID: 8382874
  59. T lymphocyte activation by cytomegalovirus-infected, allogeneic cultured human endothelial cells.
    Transplantation. 1992 Nov;54(5):887-96 PMID: 1332226
  60. Acceleration of allograft failure by cytomegalovirus.
    Curr Opin Immunol. 2007 Oct;19(5):577-82 PMID: 17716883
  61. Human effector memory CD4+ T cells directly recognize allogeneic endothelial cells in vitro and in vivo.
    J Immunol. 2007 Oct 1;179(7):4397-404 PMID: 17878335
  62. The human mixed lymphocyte-endothelium culture interaction.
    Transplantation. 1975 Jun;19(6):495-504 PMID: 166465
  63. Human cytomegalovirus latency and reactivation - a delicate balance between the virus and its host's immune system.
    Intervirology. 1999;42(5-6):314-21 PMID: 10702712
  64. Exosome-based immunotherapy.
    Cancer Immunol Immunother. 2004 Mar;53(3):234-9 PMID: 14727085
  65. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis.
    JAMA. 1989 Jun 23-30;261(24):3561-6 PMID: 2542633
  66. Human cytomegalovirus. I. Purification and characterization of viral DNA.
    J Virol. 1973 Dec;12(6):1473-81 PMID: 4128379
  67. B lymphocytes secrete antigen-presenting vesicles.
    J Exp Med. 1996 Mar 1;183(3):1161-72 PMID: 8642258
  68. Cytokine-mediated induction of endothelial adhesion molecule and histocompatibility leukocyte antigen expression by cytomegalovirus-activated T cells.
    Am J Pathol. 1996 Jan;148(1):105-19 PMID: 8546198
  69. Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes.
    Nat Immunol. 2002 Dec;3(12):1156-62 PMID: 12426563
  70. Fast screening procedures for random transposon libraries of cloned herpesvirus genomes: mutational analysis of human cytomegalovirus envelope glycoprotein genes.
    J Virol. 2000 Sep;74(17):7720-9 PMID: 10933677
  71. Human cytomegalovirus-specific CD4+-T-cell cytokine response induces fractalkine in endothelial cells.
    J Virol. 2004 Dec;78(23):13173-81 PMID: 15542669
  72. IFN-gamma enhances endothelial activation induced by tumor necrosis factor but not IL-1.
    J Immunol. 1990 Sep 15;145(6):1727-33 PMID: 1697308
  73. Release of full-length 55-kDa TNF receptor 1 in exosome-like vesicles: a mechanism for generation of soluble cytokine receptors.
    Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1297-302 PMID: 14745008
Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.182.3.1548
Published
2009-02-01
Pages
1548-59
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC2630120
Subset
IM
Grants
NHLBI NIH HHS · R01 HL051014 · United States
NHLBI NIH HHS · R01 HL051014-16 · United States
NHLBI NIH HHS · HL-051014 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.182.3.1548 PMC Full Text View journal details
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