Cytomegalovirus-infected Human Endothelial Cells Can Stimulate Allogeneic CD4+ Memory T Cells by Releasing Antigenic Exosomes

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2009 Jan 22

PMID 19155503

Citations 91

Authors

Jason D Walker

Cheryl L Maier

Jordan S Pober

Affiliations

Soon will be listed here.

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.

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References

Meuer S, Schlossman S, Reinherz E . 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; 79(14):4395-9. PMC: 346678. DOI: 10.1073/pnas.79.14.4395. View

Caby M, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C . Exosomal-like vesicles are present in human blood plasma. Int Immunol. 2005; 17(7):879-87. DOI: 10.1093/intimm/dxh267. View

Reinke P, Fietze E, Prosch S, Lippert J, Ewert R, Volk H . Late-acute renal allograft rejection and symptomless cytomegalovirus infection. Lancet. 1994; 344(8939-8940):1737-8. DOI: 10.1016/s0140-6736(94)92887-8. View

Almond P, Matas A, Gillingham K, Dunn D, Payne W, Gores P . Risk factors for chronic rejection in renal allograft recipients. Transplantation. 1993; 55(4):752-6; discussion 756-7. DOI: 10.1097/00007890-199304000-00013. View

Thery C, Boussac M, Veron P, Ricciardi-Castagnoli P, Raposo G, Garin J . Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol. 2001; 166(12):7309-18. DOI: 10.4049/jimmunol.166.12.7309. View

Compton T, Nepomuceno R, Nowlin D . Human cytomegalovirus penetrates host cells by pH-independent fusion at the cell surface. Virology. 1992; 191(1):387-95. DOI: 10.1016/0042-6822(92)90200-9. View

Pober J, Gimbrone Jr M, COTRAN R, Reiss C, Burakoff S, Fiers W . Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon. J Exp Med. 1983; 157(4):1339-53. PMC: 2186979. DOI: 10.1084/jem.157.4.1339. View

Li J, Pober J . The cathepsin B death pathway contributes to TNF plus IFN-gamma-mediated human endothelial injury. J Immunol. 2005; 175(3):1858-66. DOI: 10.4049/jimmunol.175.3.1858. View

Everett J, Hershberger R, Norman D, Chou S, Ratkovec R, Cobanoglu A . Prolonged cytomegalovirus infection with viremia is associated with development of cardiac allograft vasculopathy. J Heart Lung Transplant. 1992; 11(3 Pt 2):S133-7. View

10.

Myerson D, Hackman R, Nelson J, Ward D, McDougall J . Widespread presence of histologically occult cytomegalovirus. Hum Pathol. 1984; 15(5):430-9. DOI: 10.1016/s0046-8177(84)80076-3. View

11.

Thery C, Zitvogel L, Amigorena S . Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2(8):569-79. DOI: 10.1038/nri855. View

12.

Scholz M, Hamann A, Blaheta R, Auth M, Encke A, Markus B . 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; 35(4):230-8. DOI: 10.1016/0198-8859(92)90004-7. View

13.

Gamadia L, Remmerswaal E, Weel J, Bemelman F, van Lier R, Ten Berge I . Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood. 2002; 101(7):2686-92. DOI: 10.1182/blood-2002-08-2502. View

14.

Savage C, Hughes C, McIntyre B, Picard J, Pober J . Human CD4+ T cells proliferate to HLA-DR+ allogeneic vascular endothelium. Identification of accessory interactions. Transplantation. 1993; 56(1):128-34. DOI: 10.1097/00007890-199307000-00024. View

15.

Bolovan-Fritts C, Spector S . Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction. Blood. 2007; 111(1):175-82. PMC: 2200803. DOI: 10.1182/blood-2007-08-107730. View

16.

Waldman W, Knight D, Adams P, Orosz C, Sedmak D . In vitro induction of endothelial HLA class II antigen expression by cytomegalovirus-activated CD4+ T cells. Transplantation. 1993; 56(6):1504-12. DOI: 10.1097/00007890-199312000-00043. View

17.

Valantine H, Gao S, Menon S, Renlund D, Hunt S, Oyer P . Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: a post hoc analysis of a randomized, placebo-controlled study. Circulation. 1999; 100(1):61-6. DOI: 10.1161/01.cir.100.1.61. View

18.

Tellides G, Tereb D, Kirkiles-Smith N, Kim R, Wilson J, Schechner J . Interferon-gamma elicits arteriosclerosis in the absence of leukocytes. Nature. 2000; 403(6766):207-11. DOI: 10.1038/35003221. View

19.

Weekes M, Wills M, Sissons J, Carmichael A . Long-term stable expanded human CD4+ T cell clones specific for human cytomegalovirus are distributed in both CD45RAhigh and CD45ROhigh populations. J Immunol. 2004; 173(9):5843-51. DOI: 10.4049/jimmunol.173.9.5843. View

20.

Waldman W, Adams P, Knight D, Sedmak D . CMV as an exacerbating agent in transplant vascular sclerosis: potential immune-mediated mechanisms modelled in vitro. Transplant Proc. 1997; 29(1-2):1545-6. DOI: 10.1016/s0041-1345(96)00670-7. View