Skip to main content
Infection and Immunity logoLink to Infection and Immunity
. 1997 Apr;65(4):1317–1320. doi: 10.1128/iai.65.4.1317-1320.1997

The course of Mycobacterium tuberculosis infection in the lungs of mice lacking expression of either perforin- or granzyme-mediated cytolytic mechanisms.

A M Cooper 1, C D'Souza 1, A A Frank 1, I M Orme 1
PMCID: PMC175134  PMID: 9119468

Abstract

CD8 T cells have been shown to be protective against Mycobacterium tuberculosis infections in the mouse. These cells have been shown to be cytolytic toward M. tuberculosis-infected cells and have also been shown to release the protective cytokine gamma interferon in response to mycobacterial antigen. It has therefore been unclear how these cells mediate their protective response. To dissect this problem, we compared the courses of M. tuberculosis infections in control, perforin gene-knockout, and granzyme gene-knockout mice exposed by the realistic pulmonary route. The inability to express either of these molecules limits the expression of the major lytic pathway but does not appear to influence the course of the infection or result in any discernible histologic differences. These data seem to rule against a lytic role for CD8 T cells in the lungs and hence tend to suggest instead that another type of mechanism, such as cytokine secretion by these cells, is their primary mode of action.

Full Text

The Full Text of this article is available as a PDF (105.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Asano M., Nakane A., Kohanawa M., Minagawa T. Sequential involvement of NK cells and CD8+ T cells in granuloma formation of Rhodococcus aurantiacus-infected mice. Microbiol Immunol. 1995;39(7):499–507. doi: 10.1111/j.1348-0421.1995.tb02234.x. [DOI] [PubMed] [Google Scholar]
  2. Berman J. S., Cruikshank W. W., Center D. M., Theodore A. C., Beer D. J. Chemoattractant lymphokines specific for the helper/inducer T-lymphocyte subset. Cell Immunol. 1985 Oct 1;95(1):105–112. doi: 10.1016/0008-8749(85)90299-0. [DOI] [PubMed] [Google Scholar]
  3. Center D. M., Cruikshank W. W., Berman J. S., Beer D. J. Functional characteristics of histamine receptor-bearing mononuclear cells. I. Selective production of lymphocyte chemoattractant lymphokines with histamine used as a ligand. J Immunol. 1983 Oct;131(4):1854–1859. [PubMed] [Google Scholar]
  4. Cocchi F., DeVico A. L., Garzino-Demo A., Arya S. K., Gallo R. C., Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science. 1995 Dec 15;270(5243):1811–1815. doi: 10.1126/science.270.5243.1811. [DOI] [PubMed] [Google Scholar]
  5. Cooper A. M., Callahan J. E., Griffin J. P., Roberts A. D., Orme I. M. Old mice are able to control low-dose aerogenic infections with Mycobacterium tuberculosis. Infect Immun. 1995 Sep;63(9):3259–3265. doi: 10.1128/iai.63.9.3259-3265.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cooper A. M., Dalton D. K., Stewart T. A., Griffin J. P., Russell D. G., Orme I. M. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med. 1993 Dec 1;178(6):2243–2247. doi: 10.1084/jem.178.6.2243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cooper A. M., Roberts A. D., Rhoades E. R., Callahan J. E., Getzy D. M., Orme I. M. The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection. Immunology. 1995 Mar;84(3):423–432. [PMC free article] [PubMed] [Google Scholar]
  8. Croft M., Carter L., Swain S. L., Dutton R. W. 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. doi: 10.1084/jem.180.5.1715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cruikshank W. W., Center D. M., Nisar N., Wu M., Natke B., Theodore A. C., Kornfeld H. Molecular and functional analysis of a lymphocyte chemoattractant factor: association of biologic function with CD4 expression. Proc Natl Acad Sci U S A. 1994 May 24;91(11):5109–5113. doi: 10.1073/pnas.91.11.5109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Denkers E. Y., Scharton-Kersten T., Barbieri S., Caspar P., Sher A. A role for CD4+ NK1.1+ T lymphocytes as major histocompatibility complex class II independent helper cells in the generation of CD8+ effector function against intracellular infection. J Exp Med. 1996 Jul 1;184(1):131–139. doi: 10.1084/jem.184.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dennert G., Podack E. R. Cytolysis by H-2-specific T killer cells. Assembly of tubular complexes on target membranes. J Exp Med. 1983 May 1;157(5):1483–1495. doi: 10.1084/jem.157.5.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dhein J., Daniel P. T., Trauth B. C., Oehm A., Möller P., Krammer P. H. Induction of apoptosis by monoclonal antibody anti-APO-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens. J Immunol. 1992 Nov 15;149(10):3166–3173. [PubMed] [Google Scholar]
  13. Flynn J. L., Chan J., Triebold K. J., Dalton D. K., Stewart T. A., Bloom B. R. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993 Dec 1;178(6):2249–2254. doi: 10.1084/jem.178.6.2249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Flynn J. L., Goldstein M. M., Triebold K. J., Koller B., Bloom B. R. Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12013–12017. doi: 10.1073/pnas.89.24.12013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Griffin J. P., Orme I. M. Evolution of CD4 T-cell subsets following infection of naive and memory immune mice with Mycobacterium tuberculosis. Infect Immun. 1994 May;62(5):1683–1690. doi: 10.1128/iai.62.5.1683-1690.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hanabuchi S., Koyanagi M., Kawasaki A., Shinohara N., Matsuzawa A., Nishimura Y., Kobayashi Y., Yonehara S., Yagita H., Okumura K. Fas and its ligand in a general mechanism of T-cell-mediated cytotoxicity. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4930–4934. doi: 10.1073/pnas.91.11.4930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heusel J. W., Wesselschmidt R. L., Shresta S., Russell J. H., Ley T. J. Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell. 1994 Mar 25;76(6):977–987. doi: 10.1016/0092-8674(94)90376-x. [DOI] [PubMed] [Google Scholar]
  18. Hudig D., Ewoldt G. R., Woodard S. L. Proteases and lymphocyte cytotoxic killing mechanisms. Curr Opin Immunol. 1993 Feb;5(1):90–96. doi: 10.1016/0952-7915(93)90086-8. [DOI] [PubMed] [Google Scholar]
  19. Igietseme J. U., Magee D. M., Williams D. M., Rank R. G. Role for CD8+ T cells in antichlamydial immunity defined by Chlamydia-specific T-lymphocyte clones. Infect Immun. 1994 Nov;62(11):5195–5197. doi: 10.1128/iai.62.11.5195-5197.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ju S. T., Cui H., Panka D. J., Ettinger R., Marshak-Rothstein A. Participation of target Fas protein in apoptosis pathway induced by CD4+ Th1 and CD8+ cytotoxic T cells. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4185–4189. doi: 10.1073/pnas.91.10.4185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kägi D., Ledermann B., Bürki K., Seiler P., Odermatt B., Olsen K. J., Podack E. R., Zinkernagel R. M., Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994 May 5;369(6475):31–37. doi: 10.1038/369031a0. [DOI] [PubMed] [Google Scholar]
  22. Laberge S., Cruikshank W. W., Kornfeld H., Center D. M. Histamine-induced secretion of lymphocyte chemoattractant factor from CD8+ T cells is independent of transcription and translation. Evidence for constitutive protein synthesis and storage. J Immunol. 1995 Sep 15;155(6):2902–2910. [PubMed] [Google Scholar]
  23. Ladel C. H., Daugelat S., Kaufmann S. H. Immune response to Mycobacterium bovis bacille Calmette Guérin infection in major histocompatibility complex class I- and II-deficient knock-out mice: contribution of CD4 and CD8 T cells to acquired resistance. Eur J Immunol. 1995 Feb;25(2):377–384. doi: 10.1002/eji.1830250211. [DOI] [PubMed] [Google Scholar]
  24. Lancki D. W., Hsieh C. S., Fitch F. W. Mechanisms of lysis by cytotoxic T lymphocyte clones. Lytic activity and gene expression in cloned antigen-specific CD4+ and CD8+ T lymphocytes. J Immunol. 1991 May 1;146(9):3242–3249. [PubMed] [Google Scholar]
  25. Laochumroonvorapong P., Wang J., Liu C. C., Ye W., Moreira A. L., Elkon K. B., Freedman V. H., Kaplan G. Perforin, a cytotoxic molecule which mediates cell necrosis, is not required for the early control of mycobacterial infection in mice. Infect Immun. 1997 Jan;65(1):127–132. doi: 10.1128/iai.65.1.127-132.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Law K. F., Jagirdar J., Weiden M. D., Bodkin M., Rom W. N. Tuberculosis in HIV-positive patients: cellular response and immune activation in the lung. Am J Respir Crit Care Med. 1996 Apr;153(4 Pt 1):1377–1384. doi: 10.1164/ajrccm.153.4.8616569. [DOI] [PubMed] [Google Scholar]
  27. Lichtenheld M. G., Olsen K. J., Lu P., Lowrey D. M., Hameed A., Hengartner H., Podack E. R. Structure and function of human perforin. Nature. 1988 Sep 29;335(6189):448–451. doi: 10.1038/335448a0. [DOI] [PubMed] [Google Scholar]
  28. Magee D. M., Williams D. M., Smith J. G., Bleicker C. A., Grubbs B. G., Schachter J., Rank R. G. Role of CD8 T cells in primary Chlamydia infection. Infect Immun. 1995 Feb;63(2):516–521. doi: 10.1128/iai.63.2.516-521.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nakajima H., Henkart P. A. Cytotoxic lymphocyte granzymes trigger a target cell internal disintegration pathway leading to cytolysis and DNA breakdown. J Immunol. 1994 Feb 1;152(3):1057–1063. [PubMed] [Google Scholar]
  30. Orme I. M. Immunity to mycobacteria. Curr Opin Immunol. 1993 Aug;5(4):497–502. doi: 10.1016/0952-7915(93)90029-r. [DOI] [PubMed] [Google Scholar]
  31. Orme I. M., Miller E. S., Roberts A. D., Furney S. K., Griffin J. P., Dobos K. M., Chi D., Rivoire B., Brennan P. J. T lymphocytes mediating protection and cellular cytolysis during the course of Mycobacterium tuberculosis infection. Evidence for different kinetics and recognition of a wide spectrum of protein antigens. J Immunol. 1992 Jan 1;148(1):189–196. [PubMed] [Google Scholar]
  32. Orme I. M. The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis. J Immunol. 1987 Jan 1;138(1):293–298. [PubMed] [Google Scholar]
  33. Orme I. M. The role of CD8+ T cells in immunity to tuberculosis infection. Trends Microbiol. 1993 Jun;1(3):77–78. doi: 10.1016/0966-842x(93)90109-5. [DOI] [PubMed] [Google Scholar]
  34. Podack E. R., Young J. D., Cohn Z. A. Isolation and biochemical and functional characterization of perforin 1 from cytolytic T-cell granules. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8629–8633. doi: 10.1073/pnas.82.24.8629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rhoades E. R., Cooper A. M., Orme I. M. Chemokine response in mice infected with Mycobacterium tuberculosis. Infect Immun. 1995 Oct;63(10):3871–3877. doi: 10.1128/iai.63.10.3871-3877.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shiver J. W., Su L., Henkart P. A. Cytotoxicity with target DNA breakdown by rat basophilic leukemia cells expressing both cytolysin and granzyme A. Cell. 1992 Oct 16;71(2):315–322. doi: 10.1016/0092-8674(92)90359-k. [DOI] [PubMed] [Google Scholar]
  37. Silva C. L., Silva M. F., Pietro R. C., Lowrie D. B. Protection against tuberculosis by passive transfer with T-cell clones recognizing mycobacterial heat-shock protein 65. Immunology. 1994 Nov;83(3):341–346. [PMC free article] [PubMed] [Google Scholar]
  38. 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]
  39. Strasser A. Apoptosis. Death of a T cell. Nature. 1995 Feb 2;373(6513):385–386. doi: 10.1038/373385a0. [DOI] [PubMed] [Google Scholar]
  40. Szalay G., Ladel C. H., Kaufmann S. H. Stimulation of protective CD8+ T lymphocytes by vaccination with nonliving bacteria. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12389–12392. doi: 10.1073/pnas.92.26.12389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Walsh C. M., Matloubian M., Liu C. C., Ueda R., Kurahara C. G., Christensen J. L., Huang M. T., Young J. D., Ahmed R., Clark W. R. Immune function in mice lacking the perforin gene. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10854–10858. doi: 10.1073/pnas.91.23.10854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wynn T. A., Eltoum I., Cheever A. W., Lewis F. A., Gause W. C., Sher A. Analysis of cytokine mRNA expression during primary granuloma formation induced by eggs of Schistosoma mansoni. J Immunol. 1993 Aug 1;151(3):1430–1440. [PubMed] [Google Scholar]
  43. Young L. H., Klavinskis L. S., Oldstone M. B., Young J. D. In vivo expression of perforin by CD8+ lymphocytes during an acute viral infection. J Exp Med. 1989 Jun 1;169(6):2159–2171. doi: 10.1084/jem.169.6.2159. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES