Abstract
Mice sensitized to the G (attachment) or F (fusion) glycoproteins of respiratory syncytial virus (RSV) expressed different patterns of cytokine production and lung pathology when challenged by intranasal infection with RSV. Five days after challenge, mice sensitized to G glycoprotein produced high levels of interleukin-4 (IL-4) and IL-5 in the lungs and spleens and developed extensive pulmonary eosinophilia, while mice sensitized to F glycoprotein produced IL-2 and developed a mononuclear cell infiltration. Memory lymphocytes isolated 2 weeks after intranasal challenge of mice primed to the G or F glycoprotein secreted only IL-2 and gamma interferon (IFN-gamma) when stimulated with RSV. IL-4 and IL-5 production characteristic of Th2-type effectors in the lung was observed only after multiple rounds of in vitro stimulation of RSV G-specific memory T lymphocytes with antigen. Also IFN-gamma production appeared to play only a minor role in the expression of pulmonary pathology characteristic of Th1 or Th2 T-lymphocyte responses, because mice genetically deficient in IFN-gamma production by gene disruption displayed the same pattern of pulmonary inflammation to RSV infection after priming to RSV F or G as conventional mice. These results suggest that effector T lymphocytes exhibit a different pattern of cytokine production than memory T-lymphocyte precursors precommitted to a Th1 or Th2 pattern of differentiation. Furthermore, these observations raise the possibility that the cytokine response of human memory T lymphocytes after a single exposure to antigen in vitro may not accurately reflect the cytokine response of differentiated effector T lymphocytes at the site of infection in vivo.
Full Text
The Full Text of this article is available as a PDF (714.9 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alwan W. H., Kozlowska W. J., Openshaw P. J. Distinct types of lung disease caused by functional subsets of antiviral T cells. J Exp Med. 1994 Jan 1;179(1):81–89. doi: 10.1084/jem.179.1.81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Alwan W. H., Openshaw P. J. Distinct patterns of T- and B-cell immunity to respiratory syncytial virus induced by individual viral proteins. Vaccine. 1993;11(4):431–437. doi: 10.1016/0264-410x(93)90284-5. [DOI] [PubMed] [Google Scholar]
- Alwan W. H., Record F. M., Openshaw P. J. Phenotypic and functional characterization of T cell lines specific for individual respiratory syncytial virus proteins. J Immunol. 1993 Jun 15;150(12):5211–5218. [PubMed] [Google Scholar]
- Anderson L. J., Tsou C., Potter C., Keyserling H. L., Smith T. F., Ananaba G., Bangham C. R. Cytokine response to respiratory syncytial virus stimulation of human peripheral blood mononuclear cells. J Infect Dis. 1994 Nov;170(5):1201–1208. doi: 10.1093/infdis/170.5.1201. [DOI] [PubMed] [Google Scholar]
- Ball L. A., Young K. K., Anderson K., Collins P. L., Wertz G. W. Expression of the major glycoprotein G of human respiratory syncytial virus from recombinant vaccinia virus vectors. Proc Natl Acad Sci U S A. 1986 Jan;83(2):246–250. doi: 10.1073/pnas.83.2.246. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baumgarth N., Brown L., Jackson D., Kelso A. Novel features of the respiratory tract T-cell response to influenza virus infection: lung T cells increase expression of gamma interferon mRNA in vivo and maintain high levels of mRNA expression for interleukin-5 (IL-5) and IL-10. J Virol. 1994 Nov;68(11):7575–7581. doi: 10.1128/jvi.68.11.7575-7581.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baumgarth N., Kelso A. In vivo blockade of gamma interferon affects the influenza virus-induced humoral and the local cellular immune response in lung tissue. J Virol. 1996 Jul;70(7):4411–4418. doi: 10.1128/jvi.70.7.4411-4418.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Belosevic M., Finbloom D. S., Van Der Meide P. H., Slayter M. V., Nacy C. A. Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol. 1989 Jul 1;143(1):266–274. [PubMed] [Google Scholar]
- Bradley L. M., Atkins G. G., Swain S. L. Long-term CD4+ memory T cells from the spleen lack MEL-14, the lymph node homing receptor. J Immunol. 1992 Jan 15;148(2):324–331. [PubMed] [Google Scholar]
- Bradley L. M., Duncan D. D., Yoshimoto K., Swain S. L. Memory effectors: a potent, IL-4-secreting helper T cell population that develops in vivo after restimulation with antigen. J Immunol. 1993 Apr 15;150(8 Pt 1):3119–3130. [PubMed] [Google Scholar]
- Chin J., Magoffin R. L., Shearer L. A., Schieble J. H., Lennette E. H. Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am J Epidemiol. 1969 Apr;89(4):449–463. doi: 10.1093/oxfordjournals.aje.a120957. [DOI] [PubMed] [Google Scholar]
- Coates H. V., Alling D. W., Chanock R. M. An antigenic analysis of respiratory syncytial virus isolates by a plaque reduction neutralization test. Am J Epidemiol. 1966 Mar;83(2):299–313. doi: 10.1093/oxfordjournals.aje.a120586. [DOI] [PubMed] [Google Scholar]
- Connors M., Giese N. A., Kulkarni A. B., Firestone C. Y., Morse H. C., 3rd, Murphy B. R. Enhanced pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of interleukin-4 (IL-4) and IL-10. J Virol. 1994 Aug;68(8):5321–5325. doi: 10.1128/jvi.68.8.5321-5325.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Connors M., Kulkarni A. B., Firestone C. Y., Holmes K. L., Morse H. C., 3rd, Sotnikov A. V., Murphy B. R. Pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of CD4+ T cells. J Virol. 1992 Dec;66(12):7444–7451. doi: 10.1128/jvi.66.12.7444-7451.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dalton D. K., Pitts-Meek S., Keshav S., Figari I. S., Bradley A., Stewart T. A. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993 Mar 19;259(5102):1739–1742. doi: 10.1126/science.8456300. [DOI] [PubMed] [Google Scholar]
- Del Prete G. F., De Carli M., Mastromauro C., Biagiotti R., Macchia D., Falagiani P., Ricci M., Romagnani S. Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest. 1991 Jul;88(1):346–350. doi: 10.1172/JCI115300. [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]
- Ehlers S., Smith K. A. Differentiation of T cell lymphokine gene expression: the in vitro acquisition of T cell memory. J Exp Med. 1991 Jan 1;173(1):25–36. doi: 10.1084/jem.173.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gajewski T. F., Joyce J., Fitch F. W. Antiproliferative effect of IFN-gamma in immune regulation. III. Differential selection of TH1 and TH2 murine helper T lymphocyte clones using recombinant IL-2 and recombinant IFN-gamma. J Immunol. 1989 Jul 1;143(1):15–22. [PubMed] [Google Scholar]
- Graham B. S., Bunton L. A., Wright P. F., Karzon D. T. Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. J Clin Invest. 1991 Sep;88(3):1026–1033. doi: 10.1172/JCI115362. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Graham B. S., Perkins M. D., Wright P. F., Karzon D. T. Primary respiratory syncytial virus infection in mice. J Med Virol. 1988 Oct;26(2):153–162. doi: 10.1002/jmv.1890260207. [DOI] [PubMed] [Google Scholar]
- Graham M. B., Braciale V. L., Braciale T. J. Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection. J Exp Med. 1994 Oct 1;180(4):1273–1282. doi: 10.1084/jem.180.4.1273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heilman C. A. From the National Institute of Allergy and Infectious Diseases and the World Health Organization. Respiratory syncytial and parainfluenza viruses. J Infect Dis. 1990 Mar;161(3):402–406. doi: 10.1093/infdis/161.3.402. [DOI] [PubMed] [Google Scholar]
- Iwamoto I., Nakajima H., Endo H., Yoshida S. Interferon gamma regulates antigen-induced eosinophil recruitment into the mouse airways by inhibiting the infiltration of CD4+ T cells. J Exp Med. 1993 Feb 1;177(2):573–576. doi: 10.1084/jem.177.2.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kim H. W., Canchola J. G., Brandt C. D., Pyles G., Chanock R. M., Jensen K., Parrott R. H. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol. 1969 Apr;89(4):422–434. doi: 10.1093/oxfordjournals.aje.a120955. [DOI] [PubMed] [Google Scholar]
- Lukacher A. E., Braciale V. L., Braciale T. J. In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med. 1984 Sep 1;160(3):814–826. doi: 10.1084/jem.160.3.814. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mahanty S., King C. L., Kumaraswami V., Regunathan J., Maya A., Jayaraman K., Abrams J. S., Ottesen E. A., Nutman T. B. IL-4- and IL-5-secreting lymphocyte populations are preferentially stimulated by parasite-derived antigens in human tissue invasive nematode infections. J Immunol. 1993 Oct 1;151(7):3704–3711. [PubMed] [Google Scholar]
- Mo X. Y., Sarawar S. R., Doherty P. C. Induction of cytokines in mice with parainfluenza pneumonia. J Virol. 1995 Feb;69(2):1288–1291. doi: 10.1128/jvi.69.2.1288-1291.1995. [DOI] [PMC free article] [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. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
- Openshaw P. J., Clarke S. L., Record F. M. Pulmonary eosinophilic response to respiratory syncytial virus infection in mice sensitized to the major surface glycoprotein G. Int Immunol. 1992 Apr;4(4):493–500. doi: 10.1093/intimm/4.4.493. [DOI] [PubMed] [Google Scholar]
- Pollard A. M., Lipscomb M. F. Characterization of murine lung dendritic cells: similarities to Langerhans cells and thymic dendritic cells. J Exp Med. 1990 Jul 1;172(1):159–167. doi: 10.1084/jem.172.1.159. [DOI] [PMC free article] [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]
- Scott P. IFN-gamma modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J Immunol. 1991 Nov 1;147(9):3149–3155. [PubMed] [Google Scholar]
- Seder R. A., Paul W. E. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994;12:635–673. doi: 10.1146/annurev.iy.12.040194.003223. [DOI] [PubMed] [Google Scholar]
- Singer G. G., Abbas A. K. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity. 1994 Aug;1(5):365–371. doi: 10.1016/1074-7613(94)90067-1. [DOI] [PubMed] [Google Scholar]
- Stott E. J., Taylor G., Ball L. A., Anderson K., Young K. K., King A. M., Wertz G. W. Immune and histopathological responses in animals vaccinated with recombinant vaccinia viruses that express individual genes of human respiratory syncytial virus. J Virol. 1987 Dec;61(12):3855–3861. doi: 10.1128/jvi.61.12.3855-3861.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tang Y. W., Graham B. S. Anti-IL-4 treatment at immunization modulates cytokine expression, reduces illness, and increases cytotoxic T lymphocyte activity in mice challenged with respiratory syncytial virus. J Clin Invest. 1994 Nov;94(5):1953–1958. doi: 10.1172/JCI117546. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Webb S. R., Hutchinson J., Hayden K., Sprent J. Expansion/deletion of mature T cells exposed to endogenous superantigens in vivo. J Immunol. 1994 Jan 15;152(2):586–597. [PubMed] [Google Scholar]
- Wertz G. W., Stott E. J., Young K. K., Anderson K., Ball L. A. Expression of the fusion protein of human respiratory syncytial virus from recombinant vaccinia virus vectors and protection of vaccinated mice. J Virol. 1987 Feb;61(2):293–301. doi: 10.1128/jvi.61.2.293-301.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]