Abstract
A unique experimental model has been developed for dissecting the integrity of CD8+ T cell-mediated immunity to a persistent gammaherpesvirus under conditions of CD4+ T cell deficiency. Respiratory challenge of major histocompatibility complex class II -/- and +/+ C57BL/6J mice with the murine gammaherpesvirus 68 (MHV-68) leads to productive infection of both lung and adrenal epithelial cells. Virus titers peak within 5-10 d, and are no longer detected after day 15. Persistent, latent infection is established concurrently in splenic and lymph node B cells, with higher numbers of MHV-68+ lymphocytes being found in all lymphoid sites analyzed from the +/+ mice concurrent with the massive, but transient splenomegaly that occurred only in this group. From day 17, however, the numbers of infected B lymphocytes were consistently higher in the -/- group, while the frequency of this population diminished progressively in the +/+ controls. Infectious MHV-68 was again detected in the respiratory tract and the adrenals of the -/- (but not the +/+) mice from day 22 after infection. The titers in these sites rose progressively, with the majority of the -/- mice dying between days 120 and 133. Even so, some CD8+ effectors were still functioning as late as 100 d after infection. Depletion of CD8+ T cells at this stage led to higher virus titers in the -/- lung, and to the development of wasting in some of the -/- mice. Elimination of the CD8+ T cells from the +/+ group (day 80) increased the numbers of MHV-68+ cells in the spleen, but did not reactivate the infection in the respiratory tract. The results are consistent with the interpretation that CD8+ T cell-mediated control of this persistent gammaherpesvirus is progressively lost in the absence of the CD4+ T cell subset. This parallels what may be happening in AIDS patients who develop Kaposi's sarcoma and various Epstein Barr virus associated disease processes.
Full Text
The Full Text of this article is available as a PDF (875.7 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Allan W., Tabi Z., Cleary A., Doherty P. C. Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells. J Immunol. 1990 May 15;144(10):3980–3986. [PubMed] [Google Scholar]
- Bodmer H., Obert G., Chan S., Benoist C., Mathis D. Environmental modulation of the autonomy of cytotoxic T lymphocytes. Eur J Immunol. 1993 Jul;23(7):1649–1654. doi: 10.1002/eji.1830230738. [DOI] [PubMed] [Google Scholar]
- Borysiewicz L. K., Sissons J. G. Cytotoxic T cells and human herpes virus infections. Curr Top Microbiol Immunol. 1994;189:123–150. doi: 10.1007/978-3-642-78530-6_8. [DOI] [PubMed] [Google Scholar]
- Cardell S., Merkenschlager M., Bodmer H., Chan S., Cosgrove D., Benoist C., Mathis D. The immune system of mice lacking conventional MHC class II molecules. Adv Immunol. 1994;55:423–440. doi: 10.1016/s0065-2776(08)60515-5. [DOI] [PubMed] [Google Scholar]
- Doherty P. C., Allan W., Eichelberger M., Carding S. R. Roles of alpha beta and gamma delta T cell subsets in viral immunity. Annu Rev Immunol. 1992;10:123–151. doi: 10.1146/annurev.iy.10.040192.001011. [DOI] [PubMed] [Google Scholar]
- Doherty P. C., Tripp R. A., Sixbey J. W. Evasion of host immune responses by tumours and viruses. Ciba Found Symp. 1994;187:245–260. doi: 10.1002/9780470514672.ch16. [DOI] [PubMed] [Google Scholar]
- Efstathiou S., Ho Y. M., Hall S., Styles C. J., Scott S. D., Gompels U. A. Murine herpesvirus 68 is genetically related to the gammaherpesviruses Epstein-Barr virus and herpesvirus saimiri. J Gen Virol. 1990 Jun;71(Pt 6):1365–1372. doi: 10.1099/0022-1317-71-6-1365. [DOI] [PubMed] [Google Scholar]
- Efstathiou S., Ho Y. M., Minson A. C. Cloning and molecular characterization of the murine herpesvirus 68 genome. J Gen Virol. 1990 Jun;71(Pt 6):1355–1364. doi: 10.1099/0022-1317-71-6-1355. [DOI] [PubMed] [Google Scholar]
- Ehtisham S., Sunil-Chandra N. P., Nash A. A. Pathogenesis of murine gammaherpesvirus infection in mice deficient in CD4 and CD8 T cells. J Virol. 1993 Sep;67(9):5247–5252. doi: 10.1128/jvi.67.9.5247-5252.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eichelberger M., Allan W., Carding S. R., Bottomly K., Doherty P. C. Activation status of the CD4-8- gamma delta-T cells recovered from mice with influenza pneumonia. J Immunol. 1991 Oct 1;147(7):2069–2074. [PubMed] [Google Scholar]
- Fauci A. S. Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science. 1993 Nov 12;262(5136):1011–1018. doi: 10.1126/science.8235617. [DOI] [PubMed] [Google Scholar]
- Fung-Leung W. P., Kündig T. M., Zinkernagel R. M., Mak T. W. Immune response against lymphocytic choriomeningitis virus infection in mice without CD8 expression. J Exp Med. 1991 Dec 1;174(6):1425–1429. doi: 10.1084/jem.174.6.1425. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ganem D. AIDS. Viruses, cytokines and Kaposi's sarcoma. Curr Biol. 1995 May 1;5(5):469–471. doi: 10.1016/s0960-9822(95)00093-5. [DOI] [PubMed] [Google Scholar]
- Grusby M. J., Glimcher L. H. Immune responses in MHC class II-deficient mice. Annu Rev Immunol. 1995;13:417–435. doi: 10.1146/annurev.iy.13.040195.002221. [DOI] [PubMed] [Google Scholar]
- Grusby M. J., Johnson R. S., Papaioannou V. E., Glimcher L. H. Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice. Science. 1991 Sep 20;253(5026):1417–1420. doi: 10.1126/science.1910207. [DOI] [PubMed] [Google Scholar]
- Heslop H. E., Brenner M. K., Rooney C., Krance R. A., Roberts W. M., Rochester R., Smith C. A., Turner V., Sixbey J., Moen R. Administration of neomycin-resistance-gene-marked EBV-specific cytotoxic T lymphocytes to recipients of mismatched-related or phenotypically similar unrelated donor marrow grafts. Hum Gene Ther. 1994 Mar;5(3):381–397. doi: 10.1089/hum.1994.5.3-381. [DOI] [PubMed] [Google Scholar]
- Hou S., Doherty P. C., Zijlstra M., Jaenisch R., Katz J. M. Delayed clearance of Sendai virus in mice lacking class I MHC-restricted CD8+ T cells. J Immunol. 1992 Aug 15;149(4):1319–1325. [PubMed] [Google Scholar]
- Hou S., Fishman M., Murti K. G., Doherty P. C. Divergence between cytotoxic effector function and tumor necrosis factor alpha production for inflammatory CD4+ T cells from mice with Sendai virus pneumonia. J Virol. 1993 Oct;67(10):6299–6302. doi: 10.1128/jvi.67.10.6299-6302.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hou S., Mo X. Y., Hyland L., Doherty P. C. Host response to Sendai virus in mice lacking class II major histocompatibility complex glycoproteins. J Virol. 1995 Mar;69(3):1429–1434. doi: 10.1128/jvi.69.3.1429-1434.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jennings S. R., Bonneau R. H., Smith P. M., Wolcott R. M., Chervenak R. CD4-positive T lymphocytes are required for the generation of the primary but not the secondary CD8-positive cytolytic T lymphocyte response to herpes simplex virus in C57BL/6 mice. Cell Immunol. 1991 Mar;133(1):234–252. doi: 10.1016/0008-8749(91)90194-g. [DOI] [PubMed] [Google Scholar]
- Jonjić S., Pavić I., Polić B., Crnković I., Lucin P., Koszinowski U. H. Antibodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus. J Exp Med. 1994 May 1;179(5):1713–1717. doi: 10.1084/jem.179.5.1713. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Laufer T. M., von Herrath M. G., Grusby M. J., Oldstone M. B., Glimcher L. H. Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice. J Exp Med. 1993 Aug 1;178(2):589–596. doi: 10.1084/jem.178.2.589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lefrancois L., Goodman T. In vivo modulation of cytolytic activity and Thy-1 expression in TCR-gamma delta+ intraepithelial lymphocytes. Science. 1989 Mar 31;243(4899):1716–1718. doi: 10.1126/science.2564701. [DOI] [PubMed] [Google Scholar]
- Lehmann-Grube F., Löhler J., Utermöhlen O., Gegin C. Antiviral immune responses of lymphocytic choriomeningitis virus-infected mice lacking CD8+ T lymphocytes because of disruption of the beta 2-microglobulin gene. J Virol. 1993 Jan;67(1):332–339. doi: 10.1128/jvi.67.1.332-339.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lucin P., Pavić I., Polić B., Jonjić S., Koszinowski U. H. Gamma interferon-dependent clearance of cytomegalovirus infection in salivary glands. J Virol. 1992 Apr;66(4):1977–1984. doi: 10.1128/jvi.66.4.1977-1984.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Masucci M. G., Ernberg I. Epstein-Barr virus: adaptation to a life within the immune system. Trends Microbiol. 1994 Apr;2(4):125–130. doi: 10.1016/0966-842x(94)90599-1. [DOI] [PubMed] [Google Scholar]
- Matloubian M., Concepcion R. J., Ahmed R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol. 1994 Dec;68(12):8056–8063. doi: 10.1128/jvi.68.12.8056-8063.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moore P. S., Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med. 1995 May 4;332(18):1181–1185. doi: 10.1056/NEJM199505043321801. [DOI] [PubMed] [Google Scholar]
- Moskophidis D., Lechner F., Pircher H., Zinkernagel R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993 Apr 22;362(6422):758–761. doi: 10.1038/362758a0. [DOI] [PubMed] [Google Scholar]
- Moss D. J., Burrows S. R., Khanna R., Misko I. S., Sculley T. B. Immune surveillance against Epstein-Barr virus. Semin Immunol. 1992 Apr;4(2):97–104. [PubMed] [Google Scholar]
- Muller D., Koller B. H., Whitton J. L., LaPan K. E., Brigman K. K., Frelinger J. A. LCMV-specific, class II-restricted cytotoxic T cells in beta 2-microglobulin-deficient mice. Science. 1992 Mar 20;255(5051):1576–1578. doi: 10.1126/science.1347959. [DOI] [PubMed] [Google Scholar]
- Polić B., Jonjić S., Pavić I., Crnković I., Zorica I., Hengel H., Lucin P., Koszinowski U. H. Lack of MHC class I complex expression has no effect on spread and control of cytomegalovirus infection in vivo. J Gen Virol. 1996 Feb;77(Pt 2):217–225. doi: 10.1099/0022-1317-77-2-217. [DOI] [PubMed] [Google Scholar]
- Renne R., Zhong W., Herndier B., McGrath M., Abbey N., Kedes D., Ganem D. Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med. 1996 Mar;2(3):342–346. doi: 10.1038/nm0396-342. [DOI] [PubMed] [Google Scholar]
- Sarawar S. R., Cardin R. D., Brooks J. W., Mehrpooya M., Tripp R. A., Doherty P. C. Cytokine production in the immune response to murine gammaherpesvirus 68. J Virol. 1996 May;70(5):3264–3268. doi: 10.1128/jvi.70.5.3264-3268.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sarawar S. R., Carding S. R., Allan W., McMickle A., Fujihashi K., Kiyono H., McGhee J. R., Doherty P. C. Cytokine profiles of bronchoalveolar lavage cells from mice with influenza pneumonia: consequences of CD4+ and CD8+ T cell depletion. Reg Immunol. 1993 May-Aug;5(3-4):142–150. [PubMed] [Google Scholar]
- Sarawar S. R., Doherty P. C. Concurrent production of interleukin-2, interleukin-10, and gamma interferon in the regional lymph nodes of mice with influenza pneumonia. J Virol. 1994 May;68(5):3112–3119. doi: 10.1128/jvi.68.5.3112-3119.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sunil-Chandra N. P., Efstathiou S., Arno J., Nash A. A. Virological and pathological features of mice infected with murine gamma-herpesvirus 68. J Gen Virol. 1992 Sep;73(Pt 9):2347–2356. doi: 10.1099/0022-1317-73-9-2347. [DOI] [PubMed] [Google Scholar]
- Sunil-Chandra N. P., Efstathiou S., Nash A. A. Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo. J Gen Virol. 1992 Dec;73(Pt 12):3275–3279. doi: 10.1099/0022-1317-73-12-3275. [DOI] [PubMed] [Google Scholar]
- Tripp R. A., Hou S., Doherty P. C. Temporal loss of the activated L-selectin-low phenotype for virus-specific CD8+ memory T cells. J Immunol. 1995 Jun 1;154(11):5870–5875. [PubMed] [Google Scholar]
- Tripp R. A., Hou S., McMickle A., Houston J., Doherty P. C. Recruitment and proliferation of CD8+ T cells in respiratory virus infections. J Immunol. 1995 Jun 1;154(11):6013–6021. [PubMed] [Google Scholar]
- Tripp R. A., Lahti J. M., Doherty P. C. Laser light suicide of proliferating virus-specific CD8+ T cells in an in vivo response. J Immunol. 1995 Oct 15;155(8):3719–3721. [PubMed] [Google Scholar]
- Tripp R. A., Sarawar S. R., Doherty P. C. Characteristics of the influenza virus-specific CD8+ T cell response in mice homozygous for disruption of the H-2lAb gene. J Immunol. 1995 Sep 15;155(6):2955–2959. [PubMed] [Google Scholar]
- Usherwood E. J., Ross A. J., Allen D. J., Nash A. A. Murine gammaherpesvirus-induced splenomegaly: a critical role for CD4 T cells. J Gen Virol. 1996 Apr;77(Pt 4):627–630. doi: 10.1099/0022-1317-77-4-627. [DOI] [PubMed] [Google Scholar]
- Walling D. M., Clark N. M., Markovitz D. M., Frank T. S., Braun D. K., Eisenberg E., Krutchkoff D. J., Felix D. H., Raab-Traub N. Epstein-Barr virus coinfection and recombination in non-human immunodeficiency virus-associated oral hairy leukoplakia. J Infect Dis. 1995 May;171(5):1122–1130. doi: 10.1093/infdis/171.5.1122. [DOI] [PubMed] [Google Scholar]
- Walling D. M., Raab-Traub N. Epstein-Barr virus intrastrain recombination in oral hairy leukoplakia. J Virol. 1994 Dec;68(12):7909–7917. doi: 10.1128/jvi.68.12.7909-7917.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yao Q. Y., Rickinson A. B., Gaston J. S., Epstein M. A. In vitro analysis of the Epstein-Barr virus: host balance in long-term renal allograft recipients. Int J Cancer. 1985 Jan 15;35(1):43–49. doi: 10.1002/ijc.2910350108. [DOI] [PubMed] [Google Scholar]
- Young L., Alfieri C., Hennessy K., Evans H., O'Hara C., Anderson K. C., Ritz J., Shapiro R. S., Rickinson A., Kieff E. Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med. 1989 Oct 19;321(16):1080–1085. doi: 10.1056/NEJM198910193211604. [DOI] [PubMed] [Google Scholar]
- de Campos-Lima P. O., Levitsky V., Brooks J., Lee S. P., Hu L. F., Rickinson A. B., Masucci M. G. T cell responses and virus evolution: loss of HLA A11-restricted CTL epitopes in Epstein-Barr virus isolates from highly A11-positive populations by selective mutation of anchor residues. J Exp Med. 1994 Apr 1;179(4):1297–1305. doi: 10.1084/jem.179.4.1297. [DOI] [PMC free article] [PubMed] [Google Scholar]