Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection (original) (raw)

Abstract

T lymphocytes play a primary role in recovery from viral infections and in antiviral immunity. Although viral-specific CD8+ and CD4+ T cells have been shown to be able to lyse virally infected targets in vitro and promote recovery from lethal infection in vivo, the role of CD4+ T lymphocytes and their mechanism(s) of action in viral immunity are not well understood. The ability to further dissect the role that CD4+ T cells play in the immune response to a number of pathogens has been greatly enhanced by evidence for more extensive heterogeneity among the CD4+ T lymphocytes. To further examine the role of CD4+ T cells in the immune response to influenza infection, we have generated influenza virus-specific CD4+ T cell clones from influenza-primed BALB/c mice with differential cytokine secretion profiles that are defined as T helper type 1 (Th1) clones by the production of interleukin 2 (IL-2) and interferon gamma (IFN-gamma), or as Th2 clones by the production of IL-4, IL-5, and IL-10. Our studies have revealed that Th1 clones are cytolytic in vitro and protective against lethal challenge with virus in vivo, whereas Th2 clones are noncytolytic and not protective. Upon further evaluation of these clonal populations we have shown that not only are the Th2 clones nonprotective, but that pulmonary pathology is exacerbated as compared with control mice as evidenced by delayed viral clearance and massive pulmonary eosinophilia. These data suggest that virus-specific CD4+ T cells of the Th2 subset may not play a primary role in virus clearance and recovery and may lead to immune mediated potentiation of injury.

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Selected References

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  1. Ada G. L., Jones P. D. The immune response to influenza infection. Curr Top Microbiol Immunol. 1986;128:1–54. doi: 10.1007/978-3-642-71272-2_1. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Andrew M. E., Braciale T. J. Antigen-dependent proliferation of cloned continuous lines of H-2-restricted influenza virus-specific cytotoxic T lymphocytes. J Immunol. 1981 Sep;127(3):1201–1204. [PubMed] [Google Scholar]
  4. Araneo B. A., Woods M. L., 2nd, Daynes R. A. Reversal of the immunosenescent phenotype by dehydroepiandrosterone: hormone treatment provides an adjuvant effect on the immunization of aged mice with recombinant hepatitis B surface antigen. J Infect Dis. 1993 Apr;167(4):830–840. doi: 10.1093/infdis/167.4.830. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Bevan M. J., Cohn M. Cytotoxic effects of antigen- and mitogen-induced T cells on various targets. J Immunol. 1975 Feb;114(2 Pt 1):559–565. [PubMed] [Google Scholar]
  7. Boom W. H., Liano D., Abbas A. K. Heterogeneity of helper/inducer T lymphocytes. II. Effects of interleukin 4- and interleukin 2-producing T cell clones on resting B lymphocytes. J Exp Med. 1988 Apr 1;167(4):1350–1363. doi: 10.1084/jem.167.4.1350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Braciale T. J., Andrew M. E., Braciale V. L. Heterogeneity and specificity of cloned lines of influenza-virus specific cytotoxic T lymphocytes. J Exp Med. 1981 Apr 1;153(4):910–923. doi: 10.1084/jem.153.4.910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Braciale T. J. Immunologic recognition of influenza virus-infected cells. I. Generation of a virus-strain specific and a cross-reactive subpopulation of cytotoxic T cells in the response to type A influenza viruses of different subtypes. Cell Immunol. 1977 Oct;33(2):423–436. doi: 10.1016/0008-8749(77)90170-8. [DOI] [PubMed] [Google Scholar]
  10. Bukowski J. F., Welsh R. M. Inability of interferon to protect virus-infected cells against lysis by natural killer (NK) cells correlates with NK cell-mediated antiviral effects in vivo. J Immunol. 1985 Nov;135(5):3537–3541. [PubMed] [Google Scholar]
  11. Carding S. R., Allan W., McMickle A., Doherty P. C. Activation of cytokine genes in T cells during primary and secondary murine influenza pneumonia. J Exp Med. 1993 Feb 1;177(2):475–482. doi: 10.1084/jem.177.2.475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cher D. J., Mosmann T. R. Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol. 1987 Jun 1;138(11):3688–3694. [PubMed] [Google Scholar]
  13. Clerici M., Hakim F. T., Venzon D. J., Blatt S., Hendrix C. W., Wynn T. A., Shearer G. M. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest. 1993 Mar;91(3):759–765. doi: 10.1172/JCI116294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Fiorentino D. F., Bond M. W., Mosmann T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gajewski T. F., Lancki D. W., Stack R., Fitch F. W. "Anergy" of TH0 helper T lymphocytes induces downregulation of TH1 characteristics and a transition to a TH2-like phenotype. J Exp Med. 1994 Feb 1;179(2):481–491. doi: 10.1084/jem.179.2.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Graham M. B., Dalton D. K., Giltinan D., Braciale V. L., Stewart T. A., Braciale T. J. Response to influenza infection in mice with a targeted disruption in the interferon gamma gene. J Exp Med. 1993 Nov 1;178(5):1725–1732. doi: 10.1084/jem.178.5.1725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kanagawa O., Vaupel B. A., Gayama S., Koehler G., Kopf M. Resistance of mice deficient in IL-4 to retrovirus-induced immunodeficiency syndrome (MAIDS) Science. 1993 Oct 8;262(5131):240–242. doi: 10.1126/science.8211142. [DOI] [PubMed] [Google Scholar]
  21. Kim K. J., Kanellopoulos-Langevin C., Merwin R. M., Sachs D. H., Asofsky R. Establishment and characterization of BALB/c lymphoma lines with B cell properties. J Immunol. 1979 Feb;122(2):549–554. [PubMed] [Google Scholar]
  22. Lin Y. L., Askonas B. A. Biological properties of an influenza A virus-specific killer T cell clone. Inhibition of virus replication in vivo and induction of delayed-type hypersensitivity reactions. J Exp Med. 1981 Aug 1;154(2):225–234. doi: 10.1084/jem.154.2.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Morrison L. A., Lukacher A. E., Braciale V. L., Fan D. P., Braciale T. J. Differences in antigen presentation to MHC class I-and class II-restricted influenza virus-specific cytolytic T lymphocyte clones. J Exp Med. 1986 Apr 1;163(4):903–921. doi: 10.1084/jem.163.4.903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. 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]
  27. Palladino G., Scherle P. A., Gerhard W. Activity of CD4+ T-cell clones of type 1 and type 2 in generation of influenza virus-specific cytotoxic responses in vitro. J Virol. 1991 Nov;65(11):6071–6076. doi: 10.1128/jvi.65.11.6071-6076.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Reiner S. L., Zheng S., Wang Z. E., Stowring L., Locksley R. M. Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection. J Exp Med. 1994 Feb 1;179(2):447–456. doi: 10.1084/jem.179.2.447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Scalzo A. A., Anders E. M. Influenza viruses as lymphocyte mitogens. I. B cell mitogenesis by influenza A viruses of the H2 and H6 subtypes is controlled by the I-E/C subregion of the major histocompatibility complex. J Immunol. 1985 Feb;134(2):757–760. [PubMed] [Google Scholar]
  30. Scherle P. A., Gerhard W. Functional analysis of influenza-specific helper T cell clones in vivo. T cells specific for internal viral proteins provide cognate help for B cell responses to hemagglutinin. J Exp Med. 1986 Oct 1;164(4):1114–1128. doi: 10.1084/jem.164.4.1114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]
  32. 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]
  33. Scott P., Natovitz P., Coffman R. L., Pearce E., Sher A. Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. J Exp Med. 1988 Nov 1;168(5):1675–1684. doi: 10.1084/jem.168.5.1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Scott P., Pearce E., Cheever A. W., Coffman R. L., Sher A. Role of cytokines and CD4+ T-cell subsets in the regulation of parasite immunity and disease. Immunol Rev. 1989 Dec;112:161–182. doi: 10.1111/j.1600-065x.1989.tb00557.x. [DOI] [PubMed] [Google Scholar]
  35. Taylor P. M., Askonas B. A. Diversity in the biological properties of anti-influenza cytotoxic T cell clones. Eur J Immunol. 1983 Sep;13(9):707–711. doi: 10.1002/eji.1830130904. [DOI] [PubMed] [Google Scholar]
  36. Taylor P. M., Esquivel F., Askonas B. A. Murine CD4+ T cell clones vary in function in vitro and in influenza infection in vivo. Int Immunol. 1990;2(4):323–328. doi: 10.1093/intimm/2.4.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wong G. H., Goeddel D. V. Tumour necrosis factors alpha and beta inhibit virus replication and synergize with interferons. 1986 Oct 30-Nov 5Nature. 323(6091):819–822. doi: 10.1038/323819a0. [DOI] [PubMed] [Google Scholar]
  38. Yap K. L., Ada G. L. The recovery of mice from influenza virus infection: adoptive transfer of immunity with immune T lymphocytes. Scand J Immunol. 1978;7(5):389–397. doi: 10.1111/j.1365-3083.1978.tb00469.x. [DOI] [PubMed] [Google Scholar]
  39. Yap K. L., Braciale T. J., Ada G. L. Role of T-cell function in recovery from murine influenza infection. Cell Immunol. 1979 Mar 15;43(2):341–351. doi: 10.1016/0008-8749(79)90178-3. [DOI] [PubMed] [Google Scholar]