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Medical Microbiology and Immunology
Published in: Medical Microbiology and Immunology 2/2008

01-06-2008 | Review

The salivary glands as a privileged site of cytomegalovirus immune evasion and persistence

Authors: Ann E. Campbell, Victoria J. Cavanaugh, Jacquelyn S. Slater

Published in: Medical Microbiology and Immunology | Issue 2/2008

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Abstract

The salivary glands (SG) provide a haven for persistent cytomegalovirus replication, and in this regard are a privileged site of virus immune evasion. The murine cytomegalovirus (MCMV) model has provided insight into the immunological environment of the SG and the unqiue virus–host relationship of this organ. In response to MCMV infection, a robust T cell-mediated immune response is elicited, comprised predominantly of CD8+ T cells that phenotypically and functionally appear activated. However, they fail to clear virus by an unknown evasion mechanism that is independent of inhibitory NKG2A- or Programmed Death 1-mediated signaling. Virus is eventually eliminated from the SG by effector CD4+ T cells expressing antiviral cytokines. However, this mechanism is severely dampened by high levels of the immunosuppressive cytokine IL-10, selectively expressed by SG CD4+ T cells.
Literature
1.
Adler SP (1989) Cytomegalovirus and child day care. Evidence for an increased infection rate among day-care workers. N Engl J Med 321:1290–1296PubMedCrossRef
2.
Adler SP (1991) Cytomegalovirus and child day care: risk factors for maternal infection. Pediatr Infect Dis J 10:590–594PubMedCrossRef
3.
Adler SP (1991) Molecular epidemiology of cytomegalovirus: a study of factors affecting transmission among children at three day-care centers. Pediatr Infect Dis J 10:584–590PubMedCrossRef
4.
Adler SP (1992) Cytomegalovirus transmission and child day care. Adv Pediatr Infect Dis 7:109–122PubMed
5.
6.
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687PubMedCrossRef
7.
Bezold G, Politch JA, Kiviat NB, Kuypers JM, Wolff H, Anderson DJ (2007) Prevalence of sexually transmissible pathogens in semen from asymptomatic male infertility patients with and without leukocytospermia. Fertil Steril 87:1087–1097PubMedPubMedCentralCrossRef
8.
Bresson JL, Clavequin MC, Mazeron MC, Mengelle C, Scieux C, Segondy M, Houhou N (2003) Risk of cytomegalovirus transmission by cryopreserved semen: a study of 635 semen samples from 231 donors. Hum Reprod 18:1881–1886PubMedCrossRef
9.
Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone MB (2006) Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 12:1301–1309PubMedPubMedCentralCrossRef
10.
Bukowski JF, Welsh RM (1985) Inability of interferon to protect virus-infected cells against lysis by natural killer (NK) cells correlates with NK cell-mediated antiviral effects in vivo. J Immunol 135:3537–3541PubMedCrossRef
11.
Cavanaugh VJ, Deng Y, Birkenbach MP, Slater JS, Campbell AE (2003) Vigorous innate and virus-specific cytotoxic T-lymphocyte responses to murine cytomegalovirus in the submaxillary salivary gland. J Virol 77:1703–1717PubMedPubMedCentralCrossRef
12.
Cavanaugh VJ, Raulet DH, Campbell AE (2006) Up-regulation of CD94/NKG2A receptors and Qa-1b ligand during murine cytomegaloviirus infection of the salivary gland. J Gen Virol 88:1440–1445CrossRef
13.
Correia-Silva Jde F, Victoria JM, Guimaraes AL, Salomao UE, de Abreu MH, Bittencourt H, Gomez RS (2007) Cytomegalovirus shedding in the oral cavity of allogeneic haematopoietic stem cell transplant patients. Oral Dis 13:163–169PubMedCrossRef
14.
D’Amico G, Frascaroli G, Bianchi G, Transidico P, Doni A, Vecchi A, Sozzani S, Allavena P, Mantovani A (2000) Uncoupling of inflammatory chemokine receptors by IL-10: generation of functional decoys. Nat Immunol 1:387–391PubMedCrossRef
15.
Daniels KA, Devora G, Lai WC, O’Donnell CL, Bennett M, Welsh RM (2001) Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to ly49h. J Exp Med 194:29–44PubMedPubMedCentralCrossRef
16.
Debes GF, Dahl ME, Mahiny AJ, Bonhagen K, Campbell DJ, Siegmund K, Erb KJ, Lewis DB, Kamradt T, Hamann A (2006) Chemotactic responses of IL-4-, IL-10-, and IFN-gamma-producing CD4+ T cells depend on tissue origin and microbial stimulus. J Immunol 176:557–566PubMedCrossRef
17.
Dokun AO, Chu DT, Yang L, Bendelac AS, Yokoyama WM (2001) Analysis of in situ NK cell responses during viral infection. J Immunol 167:5286–5293PubMedCrossRef
18.
Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM, Crotty S, von Herrath MG (2006) Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med 203:2461–2472PubMedPubMedCentralCrossRef
19.
Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J Exp Med 203:2223–2227PubMedPubMedCentralCrossRef
20.
Gold MC, Munks MW, Wagner M, McMahon CW, Kelly A, Kavanagh DG, Slifka MK, Koszinowski UH, Raulet DH, Hill AB (2004) Murine cytomegalovirus interference with antigen presentation has little effect on the size or the effector memory phenotype of the CD8 T cell response. J Immunol 172:6944–6953PubMedCrossRef
21.
Gunturi A, Berg RE, Forman J (2004) The role of CD94/NKG2 in innate and adaptive immunity. Immunol Res 30:29–34PubMedCrossRef
22.
Hokeness KL, Deweerd ES, Munks MW, Lewis CA, Gladue RP, Salazar-Mather TP (2007) CXCR3-dependent recruitment of antigen-specific T lymphocytes to the liver during murine cytomegalovirus infection. J Virol 81:1241–1250PubMedCrossRef
23.
Holtappels R, Munks MW, Podlech J, Reddehase MJ (2006) CD8 T-cell-based immunotherapy of cytomegalovirus disease in the mouse model of the immunocompromised bone marrow transplant recipient, p. 383418. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic, Norfolk
24.
Humphreys IR, de Trez C, Kinkade A, Benedict CA, Croft M, Ware CF (2007) Cytomegalovirus exploits IL-10-mediated immune regulation in the salivary glands. J Exp Med 204:1217–1225PubMedPubMedCentralCrossRef
25.
Jia SH, Kurepa Z, Bai A, Forman J (2000) Comparative ability of Qdm/Qa-1b, kb, and Db to protect class Ilow cells from NK-mediated lysis in vivo. J Immunol 165:6142–6147PubMedCrossRef
26.
Jonjic S, Mutter W, Weiland F, Reddehase MJ, Koszinowski UH (1989) Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes. J Exp Med 169:1199–1212PubMedCrossRef
27.
Jonjic S, Pavic I, Lucin P, Rukavina D, Koszinowski UH (1990) Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes. J Virol 64:5457–5464PubMedPubMedCentralCrossRef
28.
Keir ME, Francisco LM, Sharpe AH (2007) PD-1 and its ligands in T-cell immunity. Curr Opin Immunol 19:309–314PubMedCrossRef
29.
Loh J, Chu DT, O’Guin AK, Yokoyama WM, Virgin HWt (2005) Natural killer cells utilize both perforin and gamma interferon to regulate murine cytomegalovirus infection in the spleen and liver. J Virol 79:661–667PubMedPubMedCentralCrossRef
30.
31.
Lu X, Pinto AK, Kelly AM, Cho KS, Hill AB (2006) Murine cytomegalovirus interference with antigen presentation contributes to the inability of CD8 T cells to control virus in the salivary gland. J Virol 80:4200–4202PubMedPubMedCentralCrossRef
32.
Lucin P, Jonjic S, Messerle M, Polic B, Hengel H, Koszinowski UH (1994) Late phase inhibition of murine cytomegalovirus replication by synergistic action of interferon-gamma and tumour necrosis factor. J Gen Virol 75(Pt 1):101–110PubMedCrossRef
33.
Matloubian M, Concepcion RJ, Ahmed R (1994) CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 68:8056–8063PubMedPubMedCentralCrossRef
34.
McMahon CW, Zajac AJ, Jamieson AM, Corral L, Hammer GE, Ahmed R, Raulet DH (2002) Viral and bacterial infections induce expression of multiple NK cell receptors in responding CD8(+) T cells. J Immunol 169:1444–1452PubMedCrossRef
35.
Mega J, Fujihashi K, Yamamoto M, McGhee JR, Hirasawa M, Kiyono H (1992) Cytokine production and T cell receptor expression by salivary gland T cells and intraepithelial T lymphocytes for the regulation of the IgA response. Adv Exp Med Biol 327:119–131PubMedCrossRef
36.
Mega J, McGhee JR, Kiyono H (1992) Cytokine- and Ig-producing T cells in mucosal effector tissues: analysis of IL-5- and IFN-gamma-producing T cells, T cell receptor expression, and IgA plasma cells from mouse salivary gland-associated tissues. J Immunol 148:2030–2039PubMedCrossRef
37.
Mega J, McGhee JR, Kiyono H (1995) Characterization of cytokine producing T cells, TCR expression, and IgA plasma cells in salivary gland-associated tissues. Adv Exp Med Biol 371B:1103–1108PubMed
38.
Meier J, Lienicke U, Tschirch E, Kruger DH, Wauer RR, Prosch S (2005) Human cytomegalovirus reactivation during lactation and mother-to-child transmission in preterm infants. J Clin Microbiol 43:1318–1324PubMedPubMedCentralCrossRef
39.
Miller JD, Peters M, Oran AE, Beresford GW, Harrington L, Boss JM, Altman JD (2002) CD94/NKG2 expression does not inhibit cytotoxic function of lymphocytic choriomeningitis virus-specific CD8+ T cells. J Immunol 169:693–701PubMedCrossRef
40.
Miller CS, Berger JR, Mootoor Y, Avdiushko SA, Zhu H, Kryscio RJ (2006) High prevalence of multiple human herpesviruses in saliva from human immunodeficiency virus-infected persons in the era of highly active antiretroviral therapy. J Clin Microbiol 44:2409–2415PubMedPubMedCentralCrossRef
41.
Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765PubMedCrossRef
42.
Moser JM, Gibbs J, Jensen PE, Lukacher AE (2002) CD94-NKG2A receptors regulate antiviral CD8(+) T cell responses. Nat Immunol 3:189–195PubMedCrossRef
43.
Neuberger P, Hamprecht K, Vochem M, Maschmann J, Speer CP, Jahn G, Poets CF, Goelz R (2006) Case–control study of symptoms and neonatal outcome of human milk-transmitted cytomegalovirus infection in premature infants. J Pediatr 148:326–331PubMedCrossRef
44.
Omarsdottir S, Casper C, Zweygberg Wirgart B, Grillner L, Vanpee M (2007) Transmission of cytomegalovirus to extremely preterm infants through breast milk. Acta Paediatr 96:492–494PubMedCrossRef
45.
Oudghiri M, Seguin J, Deslauriers N (1986) The cellular basis of salivary immunity in the mouse: incidence and distribution of B cells, T cells and macrophages in single-cell suspensions of the major salivary glands. Eur J Immunol 16:281–285PubMedCrossRef
46.
Pavic I, Polic B, Crnkovic I, Lucin P, Jonjic S, Koszinowski UH (1993) Participation of endogenous tumour necrosis factor alpha in host resistance to cytomegalovirus infection. J Gen Virol 74(Pt 10):2215–2223PubMedCrossRef
47.
Pettersson A, Sabirsh A, Bristulf J, Kidd-Ljunggren K, Ljungberg B, Owman C, Karlsson U (2005) Pro- and anti-inflammatory substances modulate expression of the leukotriene B4 receptor, BLT1, in human monocytes. J Leukoc Biol 77:1018–1025PubMedCrossRef
48.
Polic B, Jonjic S, Pavic I, Crnkovic I, Zorica I, Hengel H, Lucin P, Koszinowski UH (1996) Lack of MHC class I complex expression has no effect on spread and control of cytomegalovirus infection in vivo. J Gen Virol 77:217–225PubMedCrossRef
49.
Prins RM, Vo DD, Khan-Farooqi H, Yang MY, Soto H, Economou JS, Liau LM, Ribas A (2006) NK and CD4 cells collaborate to protect against melanoma tumor formation in the brain. J Immunol 177:8448–8455PubMedCrossRef
50.
Ribas A, Wargo JA, Comin-Anduix B, Sanetti S, Schumacher LY, McLean C, Dissette VB, Glaspy JA, McBride WH, Butterfield LH, Economou JS (2004) Enhanced tumor responses to dendritic cells in the absence of CD8-positive cells. J Immunol 172:4762–4769PubMedCrossRef
51.
Salazar-Mather TP, Hokeness KL (2006) Cytokine and chemokine networks: pathways to antiviral defense. Curr Top Microbiol Immunol 303:29–46PubMed
52.
Salazar-Mather TP, Orange JS, Biron CA (1998) Early murine cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell inflammation and protection through macrophage inflammatory protein 1alpha (MIP-1alpha)-dependent pathways. J Exp Med 187:1–14PubMedPubMedCentralCrossRef
53.
Schleiss MR (2006) Role of breast milk in acquisition of cytomegalovirus infection: recent advances. Curr Opin Pediatr 18:48–52PubMed
54.
Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ (2007) The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 8:239–245PubMedCrossRef
55.
Sheth PM, Danesh A, Sheung A, Rebbapragada A, Shahabi K, Kovacs C, Halpenny R, Tilley D, Mazzulli T, MacDonald K, Kelvin D, Kaul R (2006) Disproportionately high semen shedding of HIV is associated with compartmentalized cytomegalovirus reactivation. J Infect Dis 193:45–48PubMedCrossRef
56.
Sozzani S, Ghezzi S, Iannolo G, Luini W, Borsatti A, Polentarutti N, Sica A, Locati M, Mackay C, Wells TN, Biswas P, Vicenzi E, Poli G, Mantovani A (1998) Interleukin 10 increases CCR5 expression and HIV infection in human monocytes. J Exp Med 187:439–444PubMedPubMedCentralCrossRef
57.
Stoddart CA, Cardin RD, Boname JM, Manning WC, Abenes GB, Mocarski ES (1994) Peripheral blood mononuclear phagocytes mediate dissemination of murine cytomegalovirus. J Virol 68:6243–6253PubMedPubMedCentralCrossRef
58.
Suvas S, Azkur AK, Rouse BT (2006) Qa-1b and CD94-NKG2a interaction regulate cytolytic activity of herpes simplex virus-specific memory CD8+ T cells in the latently infected trigeminal ganglia. J Immunol 176:1703–1711PubMedCrossRef
59.
Vance RE, Jamieson AM, Cado D, Raulet DH (2002) Implications of CD94 deficiency and monoallelic NKG2A expression for natural killer cell development and repertoire formation. Proc Natl Acad Sci USA 99:868–873PubMedPubMedCentralCrossRef
60.
Wang J, Guan E, Roderiquez G, Calvert V, Alvarez R, Norcross MA (2001) Role of tyrosine phosphorylation in ligand-independent sequestration of CXCR4 in human primary monocytes-macrophages. J Biol Chem 276:49236–49243PubMedCrossRef
61.
Yasuda A, Kimura H, Hayakawa M, Ohshiro M, Kato Y, Matsuura O, Suzuki C, Morishima T (2003) Evaluation of cytomegalovirus infections transmitted via breast milk in preterm infants with a real-time polymerase chain reaction assay. Pediatrics 111:1333–1336PubMedCrossRef
Metadata
Title
The salivary glands as a privileged site of cytomegalovirus immune evasion and persistence
Authors
Ann E. Campbell
Victoria J. Cavanaugh
Jacquelyn S. Slater
Publication date
01-06-2008
Publisher
Springer Berlin Heidelberg
Published in
Medical Microbiology and Immunology / Issue 2/2008
Print ISSN: 0300-8584
Electronic ISSN: 1432-1831
DOI
https://doi.org/10.1007/s00430-008-0077-2

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