Abstract
The importance of T-lymphocyte subsets in the control of poxvirus infections is controversial. To determine the relative contribution of lymphocyte subsets important for recovery from infection with ectromelia virus (EV), a natural murine poxvirus pathogen, C57BL/6 (B6) mice lacking functional CD8+ T cells because of disruption of the beta2-microglobulin gene or lacking functional CD4+ T cells because of disruption of the I-(A)beta gene, acutely depleted of CD8+ or CD4+ T cells with monoclonal antibody, or depleted of macrophage subsets by the macrophage suicide technique were used. Recovery from infection was strictly dependent on the effector functions of CD8+ T cells, in the absence of which 100% mortality resulted. This lymphocyte population had demonstrable antiviral activity early in the infection process even before class I major histocompatibility complex (MHC)-restricted CD8+ cytotoxic T-lymphocyte (CTL) activity was detectable. CD4+ T cells were found to be necessary for the generation of an optimal virus-specific, class I MHC-restricted CD8+ CTL response and contributed to virus clearance not involving cytolytic mechanisms. In both models of CD4+ T-cell deficiency, virus clearance was incomplete and persisted at low levels in most organs and at very high levels in the skin, but the animals did not die. The elimination of macrophage subpopulations impeded virus clearance, impaired the generation of class I MHC-restricted antiviral CTL response, and resulted in 100% mortality. These findings establish an absolute requirement for CD8+ and CD4+ T lymphocytes and macrophage subsets in the elimination of a natural murine poxvirus infection and support the idea that macrophages may be essential accessory cells for the generation of class I MHC-restricted antiviral CTL responses.
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- Ahmed R., Butler L. D., Bhatti L. T4+ T helper cell function in vivo: differential requirement for induction of antiviral cytotoxic T-cell and antibody responses. J Virol. 1988 Jun;62(6):2102–2106. doi: 10.1128/jvi.62.6.2102-2106.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Battegay M., Bachmann M. F., Burhkart C., Viville S., Benoist C., Mathis D., Hengartner H., Zinkernagel R. M. Antiviral immune responses of mice lacking MHC class II or its associated invariant chain. Cell Immunol. 1996 Jan 10;167(1):115–121. doi: 10.1006/cimm.1996.0014. [DOI] [PubMed] [Google Scholar]
- Bender B. S., Croghan T., Zhang L., Small P. A., Jr Transgenic mice lacking class I major histocompatibility complex-restricted T cells have delayed viral clearance and increased mortality after influenza virus challenge. J Exp Med. 1992 Apr 1;175(4):1143–1145. doi: 10.1084/jem.175.4.1143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bennink J. R., Doherty P. C. Different rules govern help for cytotoxic T cells and B cells. Nature. 1978 Dec 21;276(5690):829–831. doi: 10.1038/276829a0. [DOI] [PubMed] [Google Scholar]
- Bevan M. J. Antigen presentation to cytotoxic T lymphocytes in vivo. J Exp Med. 1995 Sep 1;182(3):639–641. doi: 10.1084/jem.182.3.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blanden R. V. T cell response to viral and bacterial infection. Transplant Rev. 1974;19(0):56–88. doi: 10.1111/j.1600-065x.1974.tb00128.x. [DOI] [PubMed] [Google Scholar]
- Buller R. M., Holmes K. L., Hügin A., Frederickson T. N., Morse H. C., 3rd Induction of cytotoxic T-cell responses in vivo in the absence of CD4 helper cells. Nature. 1987 Jul 2;328(6125):77–79. doi: 10.1038/328077a0. [DOI] [PubMed] [Google Scholar]
- Buller R. M., Palumbo G. J. Poxvirus pathogenesis. Microbiol Rev. 1991 Mar;55(1):80–122. doi: 10.1128/mr.55.1.80-122.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen W., Drillien R., Spehner D., Buller R. M. Restricted replication of ectromelia virus in cell culture correlates with mutations in virus-encoded host range gene. Virology. 1992 Apr;187(2):433–442. doi: 10.1016/0042-6822(92)90445-u. [DOI] [PubMed] [Google Scholar]
- Clerici M., Shearer G. M. The Th1-Th2 hypothesis of HIV infection: new insights. Immunol Today. 1994 Dec;15(12):575–581. doi: 10.1016/0167-5699(94)90220-8. [DOI] [PubMed] [Google Scholar]
- Debrick J. E., Campbell P. A., Staerz U. D. Macrophages as accessory cells for class I MHC-restricted immune responses. J Immunol. 1991 Nov 1;147(9):2846–2851. [PubMed] [Google Scholar]
- Doherty P. C. Virus infections in mice with targeted gene disruptions. Curr Opin Immunol. 1993 Aug;5(4):479–483. doi: 10.1016/0952-7915(93)90026-o. [DOI] [PubMed] [Google Scholar]
- Eichelberger M., Allan W., Zijlstra M., Jaenisch R., Doherty P. C. Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J Exp Med. 1991 Oct 1;174(4):875–880. doi: 10.1084/jem.174.4.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
- FENNER F. Mouse-pox; infectious ectromelia of mice; a review. J Immunol. 1949 Dec;63(4):341–373. [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]
- 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]
- Jonjić S., Mutter W., Weiland F., Reddehase M. J., Koszinowski U. H. Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes. J Exp Med. 1989 Apr 1;169(4):1199–1212. doi: 10.1084/jem.169.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kappler J., White J., Wegmann D., Mustain E., Marrack P. Antigen presentation by Ia+ B cell hybridomas to H-2-restricted T cell hybridomas. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3604–3607. doi: 10.1073/pnas.79.11.3604. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Karupiah G., Blanden R. V., Ramshaw I. A. Interferon gamma is involved in the recovery of athymic nude mice from recombinant vaccinia virus/interleukin 2 infection. J Exp Med. 1990 Nov 1;172(5):1495–1503. doi: 10.1084/jem.172.5.1495. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Karupiah G., Coupar B. E., Andrew M. E., Boyle D. B., Phillips S. M., Müllbacher A., Blanden R. V., Ramshaw I. A. Elevated natural killer cell responses in mice infected with recombinant vaccinia virus encoding murine IL-2. J Immunol. 1990 Jan 1;144(1):290–298. [PubMed] [Google Scholar]
- Karupiah G., Fredrickson T. N., Holmes K. L., Khairallah L. H., Buller R. M. Importance of interferons in recovery from mousepox. J Virol. 1993 Jul;67(7):4214–4226. doi: 10.1128/jvi.67.7.4214-4226.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Karupiah G., Xie Q. W., Buller R. M., Nathan C., Duarte C., MacMicking J. D. Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science. 1993 Sep 10;261(5127):1445–1448. doi: 10.1126/science.7690156. [DOI] [PubMed] [Google Scholar]
- Kohonen-Corish M. R., King N. J., Woodhams C. E., Ramshaw I. A. Immunodeficient mice recover from infection with vaccinia virus expressing interferon-gamma. Eur J Immunol. 1990 Jan;20(1):157–161. doi: 10.1002/eji.1830200123. [DOI] [PubMed] [Google Scholar]
- Koller B. H., Marrack P., Kappler J. W., Smithies O. Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells. Science. 1990 Jun 8;248(4960):1227–1230. doi: 10.1126/science.2112266. [DOI] [PubMed] [Google Scholar]
- Kägi D., Ledermann B., Bürki K., Seiler P., Odermatt B., Olsen K. J., Podack E. R., Zinkernagel R. M., Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994 May 5;369(6475):31–37. doi: 10.1038/369031a0. [DOI] [PubMed] [Google Scholar]
- Kägi D., Seiler P., Pavlovic J., Ledermann B., Bürki K., Zinkernagel R. M., Hengartner H. The roles of perforin- and Fas-dependent cytotoxicity in protection against cytopathic and noncytopathic viruses. Eur J Immunol. 1995 Dec;25(12):3256–3262. doi: 10.1002/eji.1830251209. [DOI] [PubMed] [Google Scholar]
- Leist T. P., Kohler M., Zinkernagel R. M. Impaired generation of anti-viral cytotoxicity against lymphocytic choriomeningitis and vaccinia virus in mice treated with CD4-specific monoclonal antibody. Scand J Immunol. 1989 Dec;30(6):679–686. doi: 10.1111/j.1365-3083.1989.tb02476.x. [DOI] [PubMed] [Google Scholar]
- Liao N. S., Bix M., Zijlstra M., Jaenisch R., Raulet D. MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity. Science. 1991 Jul 12;253(5016):199–202. doi: 10.1126/science.1853205. [DOI] [PubMed] [Google Scholar]
- MIMS C. A. The response of mice to large intravenous injections of ectromelia virus. I. The fate of injected virus. Br J Exp Pathol. 1959 Dec;40:533–542. [PMC free article] [PubMed] [Google Scholar]
- MIMS C. A. The response of mice to large intravenous injections of ectromelia virus. II. The growth of virus in the liver. Br J Exp Pathol. 1959 Dec;40:543–550. [PMC free article] [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]
- Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045. doi: 10.1146/annurev.iy.12.040194.005015. [DOI] [PubMed] [Google Scholar]
- Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
- Mosmann T. R., Coffman R. L. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol. 1989;46:111–147. doi: 10.1016/s0065-2776(08)60652-5. [DOI] [PubMed] [Google Scholar]
- Mosmann T. R., Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996 Mar;17(3):138–146. doi: 10.1016/0167-5699(96)80606-2. [DOI] [PubMed] [Google Scholar]
- Nair S., Buiting A. M., Rouse R. J., Van Rooijen N., Huang L., Rouse B. T. Role of macrophages and dendritic cells in primary cytotoxic T lymphocyte responses. Int Immunol. 1995 Apr;7(4):679–688. doi: 10.1093/intimm/7.4.679. [DOI] [PubMed] [Google Scholar]
- Nash A. A., Jayasuriya A., Phelan J., Cobbold S. P., Waldmann H., Prospero T. Different roles for L3T4+ and Lyt 2+ T cell subsets in the control of an acute herpes simplex virus infection of the skin and nervous system. J Gen Virol. 1987 Mar;68(Pt 3):825–833. doi: 10.1099/0022-1317-68-3-825. [DOI] [PubMed] [Google Scholar]
- O'Neill H. C., Blanden R. V. Mechanisms determining innate resistance to ectromelia virus infection in C57BL mice. Infect Immun. 1983 Sep;41(3):1391–1394. doi: 10.1128/iai.41.3.1391-1394.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- O'Neill H. C., Brenan M. A role for early cytotoxic T cells in resistance to ectromelia virus infection in mice. J Gen Virol. 1987 Oct;68(Pt 10):2669–2673. doi: 10.1099/0022-1317-68-10-2669. [DOI] [PubMed] [Google Scholar]
- Pang T., McKenzie I. F., Blanden R. V. Cooperation between mouse T-cell subpopulations in the cell-mediated response to a natural poxvirus pathogen. Cell Immunol. 1976 Oct;26(2):153–159. doi: 10.1016/0008-8749(76)90359-2. [DOI] [PubMed] [Google Scholar]
- Ramshaw I., Ruby J., Ramsay A., Ada G., Karupiah G. Expression of cytokines by recombinant vaccinia viruses: a model for studying cytokines in virus infections in vivo. Immunol Rev. 1992 Jun;127:157–182. doi: 10.1111/j.1600-065x.1992.tb01413.x. [DOI] [PubMed] [Google Scholar]
- Ruby J., Ramshaw I. The antiviral activity of immune CD8+ T cells is dependent on interferon-gamma. Lymphokine Cytokine Res. 1991 Oct;10(5):353–358. [PubMed] [Google Scholar]
- Sarawar S. R., Sangster M., Coffman R. L., Doherty P. C. Administration of anti-IFN-gamma antibody to beta 2-microglobulin-deficient mice delays influenza virus clearance but does not switch the response to a T helper cell 2 phenotype. J Immunol. 1994 Aug 1;153(3):1246–1253. [PubMed] [Google Scholar]
- Spriggs M. K., Koller B. H., Sato T., Morrissey P. J., Fanslow W. C., Smithies O., Voice R. F., Widmer M. B., Maliszewski C. R. Beta 2-microglobulin-, CD8+ T-cell-deficient mice survive inoculation with high doses of vaccinia virus and exhibit altered IgG responses. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6070–6074. doi: 10.1073/pnas.89.13.6070. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [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]
- Tsuru S., Kitani H., Seno M., Abe M., Zinnaka Y., Nomoto K. Mechanism of protection during the early phase of a generalized viral infection. I. Contribution of phagocytes to protection against ectromelia virus. J Gen Virol. 1983 Sep;64(Pt 9):2021–2026. doi: 10.1099/0022-1317-64-9-2021. [DOI] [PubMed] [Google Scholar]
- Van Rooijen N., Sanders A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods. 1994 Sep 14;174(1-2):83–93. doi: 10.1016/0022-1759(94)90012-4. [DOI] [PubMed] [Google Scholar]
- Weyand C. M., Goronzy J., Swarztrauber K., Fathman C. G. Immunosuppression by anti-CD4 treatment in vivo. Cellular and humoral responses to alloantigens. Transplantation. 1989 Jun;47(6):1039–1042. doi: 10.1097/00007890-198906000-00024. [DOI] [PubMed] [Google Scholar]
- Zijlstra M., Bix M., Simister N. E., Loring J. M., Raulet D. H., Jaenisch R. Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature. 1990 Apr 19;344(6268):742–746. doi: 10.1038/344742a0. [DOI] [PubMed] [Google Scholar]
- Zinkernagel R. M., Althage A., Cooper S., Kreeb G., Klein P. A., Sefton B., Flaherty L., Stimpfling J., Shreffler D., Klein J. Ir-genes in H-2 regulate generation of anti-viral cytotoxic T cells. Mapping to K or D and dominance of unresponsiveness. J Exp Med. 1978 Aug 1;148(2):592–606. doi: 10.1084/jem.148.2.592. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zinkernagel R. M. Immunology taught by viruses. Science. 1996 Jan 12;271(5246):173–178. doi: 10.1126/science.271.5246.173. [DOI] [PubMed] [Google Scholar]
- van Rooijen N., Kors N., Kraal G. Macrophage subset repopulation in the spleen: differential kinetics after liposome-mediated elimination. J Leukoc Biol. 1989 Feb;45(2):97–104. doi: 10.1002/jlb.45.2.97. [DOI] [PubMed] [Google Scholar]