Abstract
CD4+ T cells play an important role in regulating the immune response; their contribution to virus clearance is variable. Mice that lack CD4+ T cells (CD4-/- mice) and are therefore unable to produce neutralizing antibodies cleared viscero-lymphotropic lymphocytic choriomeningitis virus (LCMV) strain WE when infected intravenously with a low dose (2 x 10(2) PFU) because of an effective CD8+ cytotoxic T-cell (CTL) response. In contrast, infection with a high dose (2 x 10(6) PFU) of LCMV strain WE led to expansion of antiviral CTL, which disappeared in CD4-/- mice; in contrast, CD4+ T-cell-competent mice developed antiviral memory CTL. This exhaustion of specific CTL caused viral persistence in CD4-/- mice, whereas CD4+ T-cell-competent mice eliminated the virus. After infection of CD4-/- mice with the faster-replicating LCMV strain DOCILE, abrogation of CTL response and establishment of viral persistence developed after infection with a low dose (5 x 10(2) PFU), i.e., an about 100-fold lower dose than in CD(4+)-competent control mice. These results show that absence of T help enhances establishment of an LCMV carrier state in selected situations.
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- 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]
- Ashman R. B., Müllbacher A. A T helper cell for anti-viral cytotoxic T-cell responses. J Exp Med. 1979 Nov 1;150(5):1277–1282. doi: 10.1084/jem.150.5.1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Battegay M., Cooper S., Althage A., Bänziger J., Hengartner H., Zinkernagel R. M. Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates. J Virol Methods. 1991 Jun;33(1-2):191–198. doi: 10.1016/0166-0934(91)90018-u. [DOI] [PubMed] [Google Scholar]
- Battegay M., Kyburz D., Hengartner H., Zinkernagel R. M. Enhancement of disease by neutralizing antiviral antibodies in the absence of primed antiviral cytotoxic T cells. Eur J Immunol. 1993 Dec;23(12):3236–3241. doi: 10.1002/eji.1830231229. [DOI] [PubMed] [Google Scholar]
- Battegay M., Moskophidis D., Waldner H., Bründler M. A., Fung-Leung W. P., Mak T. W., Hengartner H., Zinkernagel R. M. Impairment and delay of neutralizing antiviral antibody responses by virus-specific cytotoxic T cells. J Immunol. 1993 Nov 15;151(10):5408–5415. [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]
- 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]
- Borrow P., Tishon A., Oldstone M. B. Infection of lymphocytes by a virus that aborts cytotoxic T lymphocyte activity and establishes persistent infection. J Exp Med. 1991 Jul 1;174(1):203–212. doi: 10.1084/jem.174.1.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Byrne J. A., Oldstone M. B. Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus: clearance of virus in vivo. J Virol. 1984 Sep;51(3):682–686. doi: 10.1128/jvi.51.3.682-686.1984. [DOI] [PMC free article] [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. 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]
- Dunlop M. B., Blanden R. V. Mechanisms of suppression of cytotoxic T-cell responses in murine lymphocytic choriomeningitis virus infection. J Exp Med. 1977 May 1;145(5):1131–1143. doi: 10.1084/jem.145.5.1131. [DOI] [PMC free article] [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]
- Fauci A. S. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988 Feb 5;239(4840):617–622. doi: 10.1126/science.3277274. [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]
- 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]
- Lafferty K. J., Cunningham A. J. A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci. 1975 Feb;53(1):27–42. doi: 10.1038/icb.1975.3. [DOI] [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]
- 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]
- Leist T. P., Cobbold S. P., Waldmann H., Aguet M., Zinkernagel R. M. Functional analysis of T lymphocyte subsets in antiviral host defense. J Immunol. 1987 Apr 1;138(7):2278–2281. [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]
- Leung K. N., Ada G. L. Different functions of subsets of effector T cells in murine influenza virus infection. Cell Immunol. 1982 Mar 1;67(2):312–324. doi: 10.1016/0008-8749(82)90223-4. [DOI] [PubMed] [Google Scholar]
- Moskophidis D., Cobbold S. P., Waldmann H., Lehmann-Grube F. Mechanism of recovery from acute virus infection: treatment of lymphocytic choriomeningitis virus-infected mice with monoclonal antibodies reveals that Lyt-2+ T lymphocytes mediate clearance of virus and regulate the antiviral antibody response. J Virol. 1987 Jun;61(6):1867–1874. doi: 10.1128/jvi.61.6.1867-1874.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moskophidis D., Laine E., Zinkernagel R. M. Peripheral clonal deletion of antiviral memory CD8+ T cells. Eur J Immunol. 1993 Dec;23(12):3306–3311. doi: 10.1002/eji.1830231237. [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]
- Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
- O'Toole C. M., Lowdell M. W., Chargelegue D., Colvin B. T. Decline in CTL and antibody responses to HIV-1 p17 and p24 antigens in HIV-1-infected hemophiliacs irrespective of disease progression. A 5-year follow-up study. AIDS Res Hum Retroviruses. 1992 Aug;8(8):1361–1368. doi: 10.1089/aid.1992.8.1361. [DOI] [PubMed] [Google Scholar]
- Odermatt B., Eppler M., Leist T. P., Hengartner H., Zinkernagel R. M. Virus-triggered acquired immunodeficiency by cytotoxic T-cell-dependent destruction of antigen-presenting cells and lymph follicle structure. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8252–8256. doi: 10.1073/pnas.88.18.8252. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ohashi P. S., Oehen S., Buerki K., Pircher H., Ohashi C. T., Odermatt B., Malissen B., Zinkernagel R. M., Hengartner H. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991 Apr 19;65(2):305–317. doi: 10.1016/0092-8674(91)90164-t. [DOI] [PubMed] [Google Scholar]
- Pantaleo G., Koenig S., Baseler M., Lane H. C., Fauci A. S. Defective clonogenic potential of CD8+ T lymphocytes in patients with AIDS. Expansion in vivo of a nonclonogenic CD3+CD8+DR+CD25- T cell population. J Immunol. 1990 Mar 1;144(5):1696–1704. [PubMed] [Google Scholar]
- Pfau C. J., Valenti J. K., Pevear D. C., Hunt K. D. Lymphocytic choriomeningitis virus killer T cells are lethal only in weakly disseminated murine infections. J Exp Med. 1982 Jul 1;156(1):79–89. doi: 10.1084/jem.156.1.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Phillips R. E., Rowland-Jones S., Nixon D. F., Gotch F. M., Edwards J. P., Ogunlesi A. O., Elvin J. G., Rothbard J. A., Bangham C. R., Rizza C. R. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature. 1991 Dec 12;354(6353):453–459. doi: 10.1038/354453a0. [DOI] [PubMed] [Google Scholar]
- Pircher H., Moskophidis D., Rohrer U., Bürki K., Hengartner H., Zinkernagel R. M. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature. 1990 Aug 16;346(6285):629–633. doi: 10.1038/346629a0. [DOI] [PubMed] [Google Scholar]
- Quinn D. G., Zajac A. J., Frelinger J. A., Muller D. Transfer of lymphocytic choriomeningitis disease in beta 2-microglobulin-deficient mice by CD4+ T cells. Int Immunol. 1993 Oct;5(10):1193–1198. doi: 10.1093/intimm/5.10.1193. [DOI] [PubMed] [Google Scholar]
- Rahemtulla A., Fung-Leung W. P., Schilham M. W., Kündig T. M., Sambhara S. R., Narendran A., Arabian A., Wakeham A., Paige C. J., Zinkernagel R. M. Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature. 1991 Sep 12;353(6340):180–184. doi: 10.1038/353180a0. [DOI] [PubMed] [Google Scholar]
- Ramsay A. J., Ruby J., Ramshaw I. A. A case for cytokines as effector molecules in the resolution of virus infection. Immunol Today. 1993 Apr;14(4):155–157. doi: 10.1016/0167-5699(93)90277-R. [DOI] [PubMed] [Google Scholar]
- Reiss C. S., Burakoff S. J. Specificity of the helper T cell for the cytolytic T lymphocyte response to influenza viruses. J Exp Med. 1981 Aug 1;154(2):541–546. doi: 10.1084/jem.154.2.541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rosenberg Z. F., Fauci A. S. The immunopathogenesis of HIV infection. Adv Immunol. 1989;47:377–431. doi: 10.1016/s0065-2776(08)60665-3. [DOI] [PubMed] [Google Scholar]
- Scherle P. A., Palladino G., Gerhard W. Mice can recover from pulmonary influenza virus infection in the absence of class I-restricted cytotoxic T cells. J Immunol. 1992 Jan 1;148(1):212–217. [PubMed] [Google Scholar]
- Schulz M., Aichele P., Vollenweider M., Bobe F. W., Cardinaux F., Hengartner H., Zinkernagel R. M. Major histocompatibility complex--dependent T cell epitopes of lymphocytic choriomeningitis virus nucleoprotein and their protective capacity against viral disease. Eur J Immunol. 1989 Sep;19(9):1657–1667. doi: 10.1002/eji.1830190921. [DOI] [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]
- Tenner-Rácz K., Rácz P., Dietrich M., Kern P. Altered follicular dendritic cells and virus-like particles in AIDS and AIDS-related lymphadenopathy. Lancet. 1985 Jan 12;1(8420):105–106. doi: 10.1016/s0140-6736(85)91994-4. [DOI] [PubMed] [Google Scholar]
- Tishon A., Southern P. J., Oldstone M. B. Virus-lymphocyte interactions. II. Expression of viral sequences during the course of persistent lymphocytic choriomeningitis virus infection and their localization to the L3T4 lymphocyte subset. J Immunol. 1988 Feb 15;140(4):1280–1284. [PubMed] [Google Scholar]
- Walker C. M., Moody D. J., Stites D. P., Levy J. A. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science. 1986 Dec 19;234(4783):1563–1566. doi: 10.1126/science.2431484. [DOI] [PubMed] [Google Scholar]
- Whitton J. L., Southern P. J., Oldstone M. B. Analyses of the cytotoxic T lymphocyte responses to glycoprotein and nucleoprotein components of lymphocytic choriomeningitis virus. Virology. 1988 Feb;162(2):321–327. doi: 10.1016/0042-6822(88)90471-0. [DOI] [PubMed] [Google Scholar]
- Zinkernagel R. M., Moskophidis D., Kündig T., Oehen S., Pircher H., Hengartner H. Effector T-cell induction and T-cell memory versus peripheral deletion of T cells. Immunol Rev. 1993 Jun;133:199–223. doi: 10.1111/j.1600-065x.1993.tb01517.x. [DOI] [PubMed] [Google Scholar]
- Zinkernagel R. M., Welsh R. M. H-2 compatibility requirement for virus-specific T cell-mediated effector functions in vivo. I. Specificity of T cells conferring antiviral protection against lymphocytic choriomeningitis virus is associated with H-2K and H-2D. J Immunol. 1976 Nov;117(5 Pt 1):1495–1502. [PubMed] [Google Scholar]