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. 1994 Jan 1;179(1):81–89. doi: 10.1084/jem.179.1.81

Distinct types of lung disease caused by functional subsets of antiviral T cells

PMCID: PMC2191312  PMID: 8270885

Abstract

T cells appear to play a central role in viral bronchiolitis, but the effects of different functional and phenotypic subgroups of T cells have not been defined. To test the activities of T cells recognizing individual proteins of respiratory syncytial (RS) virus, virus-specific T cell lines were produced from mice primed by scarification with recombinant vaccinia viruses expressing the major surface glycoprotein (G), fusion protein (F) or second matrix (22K) protein of RS virus. As previously reported, the in vitro characteristics of these cells are predetermined by the choice of RS virus protein: 22K-specific cells are predominantly class I-restricted cytolytic CD8+ cells; F-specific cells, a mixture of cytolytic CD8+ cells and CD4+ cells with a T helper 1 cell (Th1) cytokine secretion profile, whereas those from G- sensitized mice are almost exclusively CD4+, with Th2 characteristics. Mice infected intranasally with RS virus showed mild illness and recovered fully, but developed respiratory distress after intravenous injections of T cells. Dose-for-dose, infected mice receiving G- specific cells suffered the most severe (sometimes fatal) illness, characterized by lung hemorrhage, pulmonary neutrophil recruitment (shock lung) and intense pulmonary eosinophilia. This disease was further enhanced by coinjection of 22K-specific cells, which alone caused mild shock lung without eosinophilia. F-specific cells caused minimal enhancement of pathology and had little or no effect on the disease caused by G-specific cells. Each cell line reduced lung virus titer and combined injections of G- and 22K-specific cells eliminated infection completely. The in vitro characteristics of these antiviral T cell lines therefore predict the pathological effects in vivo. Moreover, different forms of viral bronchiolitis can be caused by functionally distinct types of activated T cell.

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Selected References

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  1. 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]
  2. Alwan W. H., Record F. M., Openshaw P. J. CD4+ T cells clear virus but augment disease in mice infected with respiratory syncytial virus. Comparison with the effects of CD8+ T cells. Clin Exp Immunol. 1992 Jun;88(3):527–536. doi: 10.1111/j.1365-2249.1992.tb06482.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Baldridge J. R., Barry R. A., Hinrichs D. J. Expression of systemic protection and delayed-type hypersensitivity to Listeria monocytogenes is mediated by different T-cell subsets. Infect Immun. 1990 Mar;58(3):654–658. doi: 10.1128/iai.58.3.654-658.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. Barker D. J., Osmond C. Childhood respiratory infection and adult chronic bronchitis in England and Wales. Br Med J (Clin Res Ed) 1986 Nov 15;293(6557):1271–1275. doi: 10.1136/bmj.293.6557.1271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Binder D., Kündig T. M. Antiviral protection by CD8+ versus CD4+ T cells. CD8+ T cells correlating with cytotoxic activity in vitro are more efficient in antivaccinia virus protection than CD4-dependent IL. J Immunol. 1991 Jun 15;146(12):4301–4307. [PubMed] [Google Scholar]
  8. Bogdan C., Schröppel K., Lohoff M., Röllinghoff M., Solbach W. Immunization of susceptible hosts with a soluble antigen fraction from Leishmania major leads to aggravation of murine leishmaniasis mediated by CD4+ T cells. Eur J Immunol. 1990 Dec;20(12):2533–2540. doi: 10.1002/eji.1830201202. [DOI] [PubMed] [Google Scholar]
  9. Cannon M. J., Openshaw P. J., Askonas B. A. Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J Exp Med. 1988 Sep 1;168(3):1163–1168. doi: 10.1084/jem.168.3.1163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Caulada-Benedetti Z., al-Zamel F., Sher A., James S. Comparison of Th1- and Th2-associated immune reactivities stimulated by single versus multiple vaccination of mice with irradiated Schistosoma mansoni cercariae. J Immunol. 1991 Mar 1;146(5):1655–1660. [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. 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]
  14. Heinzel F. P., Sadick M. D., Holaday B. J., Coffman R. L., Locksley R. M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. doi: 10.1084/jem.169.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hom R. C., Finberg R. W., Mullaney S., Ruprecht R. M. Protective cellular retroviral immunity requires both CD4+ and CD8+ immune T cells. J Virol. 1991 Jan;65(1):220–224. doi: 10.1128/jvi.65.1.220-224.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hu-Li J., Ohara J., Watson C., Tsang W., Paul W. E. Derivation of a T cell line that is highly responsive to IL-4 and IL-2 (CT.4R) and of an IL-2 hyporesponsive mutant of that line (CT.4S). J Immunol. 1989 Feb 1;142(3):800–807. [PubMed] [Google Scholar]
  17. Kadima-Nzuji M., Craighead J. E. T-lymphocyte effects on murine cytomegalovirus pulmonary infection. Am J Pathol. 1990 Oct;137(4):907–912. [PMC free article] [PubMed] [Google Scholar]
  18. Karasuyama H., Melchers F. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. Eur J Immunol. 1988 Jan;18(1):97–104. doi: 10.1002/eji.1830180115. [DOI] [PubMed] [Google Scholar]
  19. Lammas D. A., Mitchell L. A., Wakelin D. Genetic control of eosinophilia. Analysis of production and response to eosinophil-differentiating factor in strains of mice infected with Trichinella spiralis. Clin Exp Immunol. 1989 Jul;77(1):137–143. [PMC free article] [PubMed] [Google Scholar]
  20. McIntosh K., Ellis E. F., Hoffman L. S., Lybass T. G., Eller J. J., Fulginiti V. A. The association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children. J Pediatr. 1973 Apr;82(4):578–590. doi: 10.1016/S0022-3476(73)80582-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. McIntosh K., Fishaut J. M. Immunopathologic mechanisms in lower respiratory tract disease of infants due to respiratory syncytial virus. Prog Med Virol. 1980;26:94–118. [PubMed] [Google Scholar]
  22. Moskophidis D., Lehmann-Grube F. Virus-induced delayed-type hypersensitivity reaction is sequentially mediated by CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci U S A. 1989 May;86(9):3291–3295. doi: 10.1073/pnas.86.9.3291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Murphy B. R., Sotnikov A. V., Lawrence L. A., Banks S. M., Prince G. A. Enhanced pulmonary histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein and challenged with RSV 3-6 months after immunization. Vaccine. 1990 Oct;8(5):497–502. doi: 10.1016/0264-410x(90)90253-i. [DOI] [PubMed] [Google Scholar]
  24. Muñoz J. L., McCarthy C. A., Clark M. E., Hall C. B. Respiratory syncytial virus infection in C57BL/6 mice: clearance of virus from the lungs with virus-specific cytotoxic T cells. J Virol. 1991 Aug;65(8):4494–4497. doi: 10.1128/jvi.65.8.4494-4497.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Openshaw P. J., Anderson K., Wertz G. W., Askonas B. A. The 22,000-kilodalton protein of respiratory syncytial virus is a major target for Kd-restricted cytotoxic T lymphocytes from mice primed by infection. J Virol. 1990 Apr;64(4):1683–1689. doi: 10.1128/jvi.64.4.1683-1689.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Openshaw P. J. Flow cytometric analysis of pulmonary lymphocytes from mice infected with respiratory syncytial virus. Clin Exp Immunol. 1989 Feb;75(2):324–328. [PMC free article] [PubMed] [Google Scholar]
  29. Openshaw P. J., Pemberton R. M., Ball L. A., Wertz G. W., Askonas B. A. Helper T cell recognition of respiratory syncytial virus in mice. J Gen Virol. 1988 Feb;69(Pt 2):305–312. doi: 10.1099/0022-1317-69-2-305. [DOI] [PubMed] [Google Scholar]
  30. Pattemore P. K., Johnston S. L., Bardin P. G. Viruses as precipitants of asthma symptoms. I. Epidemiology. Clin Exp Allergy. 1992 Mar;22(3):325–336. doi: 10.1111/j.1365-2222.1992.tb03094.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pemberton R. M., Cannon M. J., Openshaw P. J., Ball L. A., Wertz G. W., Askonas B. A. Cytotoxic T cell specificity for respiratory syncytial virus proteins: fusion protein is an important target antigen. J Gen Virol. 1987 Aug;68(Pt 8):2177–2182. doi: 10.1099/0022-1317-68-8-2177. [DOI] [PubMed] [Google Scholar]
  32. Robinson D. S., Hamid Q., Ying S., Tsicopoulos A., Barkans J., Bentley A. M., Corrigan C., Durham S. R., Kay A. B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992 Jan 30;326(5):298–304. doi: 10.1056/NEJM199201303260504. [DOI] [PubMed] [Google Scholar]
  33. Schumacher J. H., O'Garra A., Shrader B., van Kimmenade A., Bond M. W., Mosmann T. R., Coffman R. L. The characterization of four monoclonal antibodies specific for mouse IL-5 and development of mouse and human IL-5 enzyme-linked immunosorbent. J Immunol. 1988 Sep 1;141(5):1576–1581. [PubMed] [Google Scholar]
  34. Sly P. D., Hibbert M. E. Childhood asthma following hospitalization with acute viral bronchiolitis in infancy. Pediatr Pulmonol. 1989;7(3):153–158. doi: 10.1002/ppul.1950070307. [DOI] [PubMed] [Google Scholar]
  35. Stott E. J., Ball L. A., Young K. K., Furze J., Wertz G. W. Human respiratory syncytial virus glycoprotein G expressed from a recombinant vaccinia virus vector protects mice against live-virus challenge. J Virol. 1986 Nov;60(2):607–613. doi: 10.1128/jvi.60.2.607-613.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Street N. E., Schumacher J. H., Fong T. A., Bass H., Fiorentino D. F., Leverah J. A., Mosmann T. R. Heterogeneity of mouse helper T cells. Evidence from bulk cultures and limiting dilution cloning for precursors of Th1 and Th2 cells. J Immunol. 1990 Mar 1;144(5):1629–1639. [PubMed] [Google Scholar]
  38. Vaux-Peretz F., Chapsal J. M., Meignier B. Comparison of the ability of formalin-inactivated respiratory syncytial virus, immunopurified F, G and N proteins and cell lysate to enhance pulmonary changes in Balb/c mice. Vaccine. 1992;10(2):113–118. doi: 10.1016/0264-410x(92)90027-h. [DOI] [PubMed] [Google Scholar]
  39. Vaux-Peretz F., Meignier B. Comparison of lung histopathology and bronchoalveolar lavage cytology in mice and cotton rats infected with respiratory syncytial virus. Vaccine. 1990 Dec;8(6):543–548. doi: 10.1016/0264-410x(90)90005-7. [DOI] [PubMed] [Google Scholar]
  40. Wathen M. W., Kakuk T. J., Brideau R. J., Hausknecht E. C., Cole S. L., Zaya R. M. Vaccination of cotton rats with a chimeric FG glycoprotein of human respiratory syncytial virus induces minimal pulmonary pathology on challenge. J Infect Dis. 1991 Mar;163(3):477–482. doi: 10.1093/infdis/163.3.477. [DOI] [PubMed] [Google Scholar]
  41. 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]

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