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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1997 May 1; 99(9): 2183–2191.
PMCID: PMC508048

T cell source of type 1 cytokines determines illness patterns in respiratory syncytial virus-infected mice.


Manipulation of the cytokine microenvironment at the time of vaccination can influence immune responses to remote challenge, providing a strategy to study the molecular pathogenesis of respiratory syncytial virus (RSV) vaccine-enhanced disease in the mouse model. Although treatment with antibody against IL-4 or recombinant IL-12 (rIL-12) at the time of formalin-inactivated RSV vaccination induced a similar shift in the pattern of cytokine mRNA expression upon live virus challenge, anti-IL-4 treated mice had increased CD8+ cytotoxic T lymphocyte activity and reduced illness compared with rIL-12-treated mice. To define effector mechanisms responsible for these patterns, CD4+ and/or CD8+ T lymphocytes were selectively depleted in vivo at the time of RSV challenge. In rIL-12-treated mice, CD4+ lymphocytes made the largest contribution to IFN-gamma mRNA, RSV clearance, and illness, while in anti-IL-4 treated mice, CD8+ lymphocytes were the major effector. The effector responsible for virus clearance also mediated illness, suggesting that efficiency of virus clearance determined disease expression. These results demonstrate that the phenotype of effector cells involved in the immune response to virus challenge may be a more important determinant of disease than patterns of cytokine expression classically assigned to Th1 and Th2 lymphocytes.

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Selected References

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  • Hall CB. Prospects for a respiratory syncytial virus vaccine. Science. 1994 Sep 2;265(5177):1393–1394. [PubMed]
  • Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol. 1969 Apr;89(4):405–421. [PubMed]
  • Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, Parrott RH. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol. 1969 Apr;89(4):422–434. [PubMed]
  • Fulginiti VA, Eller JJ, Sieber OF, Joyner JW, Minamitani M, Meiklejohn G. Respiratory virus immunization. I. A field trial of two inactivated respiratory virus vaccines; an aqueous trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. Am J Epidemiol. 1969 Apr;89(4):435–448. [PubMed]
  • Chin J, Magoffin RL, Shearer LA, Schieble JH, Lennette EH. 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. [PubMed]
  • Kim HW, Arrobio JO, Pyles G, Brandt CD, Camargo E, Chanock RM, Parrott RH. Clinical and immunological response of infants and children to administration of low-temperature adapted respiratory syncytial virus. Pediatrics. 1971 Nov;48(5):745–755. [PubMed]
  • Wright PF, v Mills J, Chanock RM. Evaluation of a temperature-sensitive mutant of respiratory syncytial virus in adults. J Infect Dis. 1971 Nov;124(5):505–511. [PubMed]
  • Murphy BR, Hall SL, Kulkarni AB, Crowe JE, Jr, Collins PL, Connors M, Karron RA, Chanock RM. An update on approaches to the development of respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) vaccines. Virus Res. 1994 Apr;32(1):13–36. [PubMed]
  • Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. 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]
  • Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. [PubMed]
  • Erard F, Wild MT, Garcia-Sanz JA, Le Gros G. Switch of CD8 T cells to noncytolytic CD8-CD4- cells that make TH2 cytokines and help B cells. Science. 1993 Jun 18;260(5115):1802–1805. [PubMed]
  • Croft M, Carter L, Swain SL, Dutton RW. Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin (IL)-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles. J Exp Med. 1994 Nov 1;180(5):1715–1728. [PMC free article] [PubMed]
  • Ferrick DA, Schrenzel MD, Mulvania T, Hsieh B, Ferlin WG, Lepper H. Differential production of interferon-gamma and interleukin-4 in response to Th1- and Th2-stimulating pathogens by gamma delta T cells in vivo. Nature. 1995 Jan 19;373(6511):255–257. [PubMed]
  • Scharton TM, Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J Exp Med. 1993 Aug 1;178(2):567–577. [PMC free article] [PubMed]
  • Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O'Garra A, Murphy KM. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. [PubMed]
  • Scott P, Natovitz P, Sher A. B lymphocytes are required for the generation of T cells that mediate healing of cutaneous leishmaniasis. J Immunol. 1986 Aug 1;137(3):1017–1021. [PubMed]
  • Shankar AH, Titus RG. T cell and non-T cell compartments can independently determine resistance to Leishmania major. J Exp Med. 1995 Mar 1;181(3):845–855. [PMC free article] [PubMed]
  • Sadick MD, Locksley RM, Tubbs C, Raff HV. Murine cutaneous leishmaniasis: resistance correlates with the capacity to generate interferon-gamma in response to Leishmania antigens in vitro. J Immunol. 1986 Jan;136(2):655–661. [PubMed]
  • Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM. 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. [PMC free article] [PubMed]
  • Gazzinelli RT, Hakim FT, Hieny S, Shearer GM, Sher A. Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine. J Immunol. 1991 Jan 1;146(1):286–292. [PubMed]
  • Sher A, Coffman RL, Hieny S, Cheever AW. Ablation of eosinophil and IgE responses with anti-IL-5 or anti-IL-4 antibodies fails to affect immunity against Schistosoma mansoni in the mouse. J Immunol. 1990 Dec 1;145(11):3911–3916. [PubMed]
  • Romani L, Mocci S, Bietta C, Lanfaloni L, Puccetti P, Bistoni F. Th1 and Th2 cytokine secretion patterns in murine candidiasis: association of Th1 responses with acquired resistance. Infect Immun. 1991 Dec;59(12):4647–4654. [PMC free article] [PubMed]
  • Yamamura M, Uyemura K, Deans RJ, Weinberg K, Rea TH, Bloom BR, Modlin RL. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. [PubMed]
  • Griffin DE, Ward BJ. Differential CD4 T cell activation in measles. J Infect Dis. 1993 Aug;168(2):275–281. [PubMed]
  • Clerici M, Hakim FT, Venzon DJ, Blatt S, Hendrix CW, Wynn TA, Shearer GM. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest. 1993 Mar;91(3):759–765. [PMC free article] [PubMed]
  • Graham BS, Henderson GS, Tang YW, Lu X, Neuzil KM, Colley DG. Priming immunization determines T helper cytokine mRNA expression patterns in lungs of mice challenged with respiratory syncytial virus. J Immunol. 1993 Aug 15;151(4):2032–2040. [PubMed]
  • Tang YW, Graham BS. 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. [PMC free article] [PubMed]
  • Tang YW, Graham BS. Interleukin-12 treatment during immunization elicits a T helper cell type 1-like immune response in mice challenged with respiratory syncytial virus and improves vaccine immunogenicity. J Infect Dis. 1995 Sep;172(3):734–738. [PubMed]
  • Noben-Trauth N, Kropf P, Müller I. Susceptibility to Leishmania major infection in interleukin-4-deficient mice. Science. 1996 Feb 16;271(5251):987–990. [PubMed]
  • Graham BS, Perkins MD, Wright PF, Karzon DT. Primary respiratory syncytial virus infection in mice. J Med Virol. 1988 Oct;26(2):153–162. [PubMed]
  • Schoenhaut DS, Chua AO, Wolitzky AG, Quinn PM, Dwyer CM, McComas W, Familletti PC, Gately MK, Gubler U. Cloning and expression of murine IL-12. J Immunol. 1992 Jun 1;148(11):3433–3440. [PubMed]
  • Wolf SF, Temple PA, Kobayashi M, Young D, Dicig M, Lowe L, Dzialo R, Fitz L, Ferenz C, Hewick RM, et al. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol. 1991 May 1;146(9):3074–3081. [PubMed]
  • Ohara J, Paul WE. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature. 1985 May 23;315(6017):333–336. [PubMed]
  • Dialynas DP, Quan ZS, Wall KA, Pierres A, Quintáns J, Loken MR, Pierres M, Fitch FW. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983 Nov;131(5):2445–2451. [PubMed]
  • Sarmiento M, Glasebrook AL, Fitch FW. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980 Dec;125(6):2665–2672. [PubMed]
  • Graham BS, Bunton LA, Wright PF, Karzon DT. 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. [PMC free article] [PubMed]
  • Kim HW, Leikin SL, Arrobio J, Brandt CD, Chanock RM, Parrott RH. Cell-mediated immunity to respiratory syncytial virus induced by inactivated vaccine or by infection. Pediatr Res. 1976 Jan;10(1):75–78. [PubMed]
  • Alwan WH, Kozlowska WJ, Openshaw PJ. Distinct types of lung disease caused by functional subsets of antiviral T cells. J Exp Med. 1994 Jan 1;179(1):81–89. [PMC free article] [PubMed]
  • Connors M, Kulkarni AB, Firestone CY, Holmes KL, Morse HC, 3rd, Sotnikov AV, Murphy BR. 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. [PMC free article] [PubMed]
  • Alwan WH, Record FM, Openshaw PJ. 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]
  • Audibert FM, Lise LD. Adjuvants: current status, clinical perspectives and future prospects. Immunol Today. 1993 Jun;14(6):281–284. [PubMed]
  • Playfair JH, De Souza JB. Recombinant gamma interferon is a potent adjuvant for a malaria vaccine in mice. Clin Exp Immunol. 1987 Jan;67(1):5–10. [PubMed]
  • Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. [PMC free article] [PubMed]
  • Stern AS, Podlaski FJ, Hulmes JD, Pan YC, Quinn PM, Wolitzky AG, Familletti PC, Stremlo DL, Truitt T, Chizzonite R, et al. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6808–6812. [PubMed]
  • Afonso LC, Scharton TM, Vieira LQ, Wysocka M, Trinchieri G, Scott P. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science. 1994 Jan 14;263(5144):235–237. [PubMed]
  • Wynn TA, Eltoum I, Oswald IP, Cheever AW, Sher A. Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology. J Exp Med. 1994 May 1;179(5):1551–1561. [PMC free article] [PubMed]
  • Wynn TA, Cheever AW, Jankovic D, Poindexter RW, Caspar P, Lewis FA, Sher A. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature. 1995 Aug 17;376(6541):594–596. [PubMed]
  • Schijns VE, Haagmans BL, Horzinek MC. IL-12 stimulates an antiviral type 1 cytokine response but lacks adjuvant activity in IFN-gamma-receptor-deficient mice. J Immunol. 1995 Sep 1;155(5):2525–2532. [PubMed]
  • Cannon MJ, Openshaw PJ, Askonas BA. 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. [PMC free article] [PubMed]
  • Taylor G, Thomas LH, Wyld SG, Furze J, Sopp P, Howard CJ. Role of T-lymphocyte subsets in recovery from respiratory syncytial virus infection in calves. J Virol. 1995 Nov;69(11):6658–6664. [PMC free article] [PubMed]
  • Bangham CR, McMichael AJ. Specific human cytotoxic T cells recognize B-cell lines persistently infected with respiratory syncytial virus. Proc Natl Acad Sci U S A. 1986 Dec;83(23):9183–9187. [PubMed]
  • Chiba Y, Minagawa T, Mito K, Nakane A, Suga K, Honjo T, Nakao T. Effect of breast feeding on responses of systemic interferon and virus-specific lymphocyte transformation in infants with respiratory syncytial virus infection. J Med Virol. 1987 Jan;21(1):7–14. [PubMed]
  • Isaacs D, Bangham CR, McMichael AJ. Cell-mediated cytotoxic response to respiratory syncytial virus in infants with bronchiolitis. Lancet. 1987 Oct 3;2(8562):769–771. [PubMed]
  • Orange JS, Wolf SF, Biron CA. Effects of IL-12 on the response and susceptibility to experimental viral infections. J Immunol. 1994 Feb 1;152(3):1253–1264. [PubMed]
  • Orange JS, Salazar-Mather TP, Opal SM, Spencer RL, Miller AH, McEwen BS, Biron CA. Mechanism of interleukin 12-mediated toxicities during experimental viral infections: role of tumor necrosis factor and glucocorticoids. J Exp Med. 1995 Mar 1;181(3):901–914. [PMC free article] [PubMed]
  • Havran WL, Allison JP. Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature. 1988 Sep 29;335(6189):443–445. [PubMed]
  • Carding SR, Allan W, Kyes S, Hayday A, Bottomly K, Doherty PC. Late dominance of the inflammatory process in murine influenza by gamma/delta + T cells. J Exp Med. 1990 Oct 1;172(4):1225–1231. [PMC free article] [PubMed]
  • Hiromatsu K, Yoshikai Y, Matsuzaki G, Ohga S, Muramori K, Matsumoto K, Bluestone JA, Nomoto K. A protective role of gamma/delta T cells in primary infection with Listeria monocytogenes in mice. J Exp Med. 1992 Jan 1;175(1):49–56. [PMC free article] [PubMed]
  • Barnes PF, Grisso CL, Abrams JS, Band H, Rea TH, Modlin RL. Gamma delta T lymphocytes in human tuberculosis. J Infect Dis. 1992 Mar;165(3):506–512. [PubMed]
  • Mombaerts P, Arnoldi J, Russ F, Tonegawa S, Kaufmann SH. Different roles of alpha beta and gamma delta T cells in immunity against an intracellular bacterial pathogen. Nature. 1993 Sep 2;365(6441):53–56. [PubMed]
  • Skeen MJ, Ziegler HK. Induction of murine peritoneal gamma/delta T cells and their role in resistance to bacterial infection. J Exp Med. 1993 Sep 1;178(3):971–984. [PMC free article] [PubMed]
  • Fu YX, Roark CE, Kelly K, Drevets D, Campbell P, O'Brien R, Born W. Immune protection and control of inflammatory tissue necrosis by gamma delta T cells. J Immunol. 1994 Oct 1;153(7):3101–3115. [PubMed]
  • Haas W, Pereira P, Tonegawa S. Gamma/delta cells. Annu Rev Immunol. 1993;11:637–685. [PubMed]
  • Cesano A, Visonneau S, Clark SC, Santoli D. Cellular and molecular mechanisms of activation of MHC nonrestricted cytotoxic cells by IL-12. J Immunol. 1993 Sep 15;151(6):2943–2957. [PubMed]
  • Skeen MJ, Ziegler HK. Activation of gamma delta T cells for production of IFN-gamma is mediated by bacteria via macrophage-derived cytokines IL-1 and IL-12. J Immunol. 1995 Jun 1;154(11):5832–5841. [PubMed]

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