Skip to main content
Infection and Immunity logoLink to Infection and Immunity
. 1996 May;64(5):1744–1749. doi: 10.1128/iai.64.5.1744-1749.1996

Control of natural killer cell-mediated innate resistance against the intracellular pathogen Listeria monocytogenes by gamma/delta T lymphocytes.

C H Ladel 1, C Blum 1, S H Kaufmann 1
PMCID: PMC173987  PMID: 8613386

Abstract

Listeria monocytogenes is an intracellular bacterium which causes an acute infectious disease in mice. Initial host resistance depends on innate immunity mediated primarily by natural killer (NK) cells followed by specific alpha/beta T cells, which are central to acquired specific immunity. Gamma/delta T lymphocytes seem to provide a link between the innate and the specific immune response. All these lymphocyte populations produce gamma interferon (IFN-gamma), which, because of its macrophage-activating potential, is central to antibacterial protection. IFN-gamma from NK cells not only contributes to early host resistance but also promotes development of protective T-cell responses of helper T type 1 (Th1) type. Here, we show that innate resistance and early IFN-gamma production in listeriosis are markedly impaired in T-cell receptor (TCR)-delta-/- but not TCR-beta-/- gene disruption mutant mice. By two-color cytofluorimetry, we demonstrate that NK cells rather than gamma/delta T lymphocytes are the major cellular source of IFN-gamma in immunocompetent mice and that IFN-gamma production by NK cells is impaired in the TCR-delta-/- mutants. Probably, reduced tumor necrosis factor production in listeria-infected TCR-delta-/- mutants contributed to impaired NK cell activation. Our data reveal a novel function of gamma/delta T cells as regulators of innate resistance against sublethal infection with an intracellular pathogen.

Full Text

The Full Text of this article is available as a PDF (339.2 KB).

Selected References

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

  1. Assenmacher M., Schmitz J., Radbruch A. Flow cytometric determination of cytokines in activated murine T helper lymphocytes: expression of interleukin-10 in interferon-gamma and in interleukin-4-expressing cells. Eur J Immunol. 1994 May;24(5):1097–1101. doi: 10.1002/eji.1830240513. [DOI] [PubMed] [Google Scholar]
  2. Bancroft G. J., Schreiber R. D., Unanue E. R. Natural immunity: a T-cell-independent pathway of macrophage activation, defined in the scid mouse. Immunol Rev. 1991 Dec;124:5–24. doi: 10.1111/j.1600-065x.1991.tb00613.x. [DOI] [PubMed] [Google Scholar]
  3. Bancroft G. J. The role of natural killer cells in innate resistance to infection. Curr Opin Immunol. 1993 Aug;5(4):503–510. doi: 10.1016/0952-7915(93)90030-v. [DOI] [PubMed] [Google Scholar]
  4. Correa I., Raulet D. H. Binding of diverse peptides to MHC class I molecules inhibits target cell lysis by activated natural killer cells. Immunity. 1995 Jan;2(1):61–71. doi: 10.1016/1074-7613(95)90079-9. [DOI] [PubMed] [Google Scholar]
  5. Dunn P. L., North R. J. Resolution of primary murine listeriosis and acquired resistance to lethal secondary infection can be mediated predominantly by Thy-1+ CD4- CD8- cells. J Infect Dis. 1991 Nov;164(5):869–877. doi: 10.1093/infdis/164.5.869. [DOI] [PubMed] [Google Scholar]
  6. Emoto M., Nishimura H., Sakai T., Hiromatsu K., Gomi H., Itohara S., Yoshikai Y. Mice deficient in gamma delta T cells are resistant to lethal infection with Salmonella choleraesuis. Infect Immun. 1995 Sep;63(9):3736–3738. doi: 10.1128/iai.63.9.3736-3738.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ferrick D. A., Schrenzel M. D., Mulvania T., Hsieh B., Ferlin W. G., 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. doi: 10.1038/373255a0. [DOI] [PubMed] [Google Scholar]
  8. Flesch I. E., Hess J. H., Huang S., Aguet M., Rothe J., Bluethmann H., Kaufmann S. H. Early interleukin 12 production by macrophages in response to mycobacterial infection depends on interferon gamma and tumor necrosis factor alpha. J Exp Med. 1995 May 1;181(5):1615–1621. doi: 10.1084/jem.181.5.1615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hiromatsu K., Yoshikai Y., Matsuzaki G., Ohga S., Muramori K., Matsumoto K., Bluestone J. A., 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. doi: 10.1084/jem.175.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  11. Itohara S., Mombaerts P., Lafaille J., Iacomini J., Nelson A., Clarke A. R., Hooper M. L., Farr A., Tonegawa S. T cell receptor delta gene mutant mice: independent generation of alpha beta T cells and programmed rearrangements of gamma delta TCR genes. Cell. 1993 Feb 12;72(3):337–348. doi: 10.1016/0092-8674(93)90112-4. [DOI] [PubMed] [Google Scholar]
  12. Jung T., Schauer U., Heusser C., Neumann C., Rieger C. Detection of intracellular cytokines by flow cytometry. J Immunol Methods. 1993 Feb 26;159(1-2):197–207. doi: 10.1016/0022-1759(93)90158-4. [DOI] [PubMed] [Google Scholar]
  13. Kaufmann S. H. Immunity to intracellular bacteria. Annu Rev Immunol. 1993;11:129–163. doi: 10.1146/annurev.iy.11.040193.001021. [DOI] [PubMed] [Google Scholar]
  14. Kaufmann S. H., Ladel C. H. Application of knockout mice to the experimental analysis of infections with bacteria and protozoa. Trends Microbiol. 1994 Jul;2(7):235–242. doi: 10.1016/0966-842x(94)90628-9. [DOI] [PubMed] [Google Scholar]
  15. Kärre K. Express yourself or die: peptides, MHC molecules, and NK cells. Science. 1995 Feb 17;267(5200):978–979. doi: 10.1126/science.7863341. [DOI] [PubMed] [Google Scholar]
  16. Ladel C. H., Flesch I. E., Arnoldi J., Kaufmann S. H. Studies with MHC-deficient knock-out mice reveal impact of both MHC I- and MHC II-dependent T cell responses on Listeria monocytogenes infection. J Immunol. 1994 Oct 1;153(7):3116–3122. [PubMed] [Google Scholar]
  17. Leist T. P., Meager A., Exley T., Zinkernagel R. M. Evidence for a role of IFN gamma in control of Listeria monocytogenes in T cell deficient mice. Experientia. 1991 Jun 15;47(6):630–632. doi: 10.1007/BF01949893. [DOI] [PubMed] [Google Scholar]
  18. Malnati M. S., Peruzzi M., Parker K. C., Biddison W. E., Ciccone E., Moretta A., Long E. O. Peptide specificity in the recognition of MHC class I by natural killer cell clones. Science. 1995 Feb 17;267(5200):1016–1018. doi: 10.1126/science.7863326. [DOI] [PubMed] [Google Scholar]
  19. McKnight A. J., Zimmer G. J., Fogelman I., Wolf S. F., Abbas A. K. Effects of IL-12 on helper T cell-dependent immune responses in vivo. J Immunol. 1994 Mar 1;152(5):2172–2179. [PubMed] [Google Scholar]
  20. Meager A., Leung H., Woolley J. Assays for tumour necrosis factor and related cytokines. J Immunol Methods. 1989 Jan 6;116(1):1–17. doi: 10.1016/0022-1759(89)90306-2. [DOI] [PubMed] [Google Scholar]
  21. Mombaerts P., Arnoldi J., Russ F., Tonegawa S., Kaufmann S. H. 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. doi: 10.1038/365053a0. [DOI] [PubMed] [Google Scholar]
  22. Mombaerts P., Clarke A. R., Rudnicki M. A., Iacomini J., Itohara S., Lafaille J. J., Wang L., Ichikawa Y., Jaenisch R., Hooper M. L. Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Nature. 1992 Nov 19;360(6401):225–231. doi: 10.1038/360225a0. [DOI] [PubMed] [Google Scholar]
  23. Mombaerts P., Iacomini J., Johnson R. S., Herrup K., Tonegawa S., Papaioannou V. E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. doi: 10.1016/0092-8674(92)90030-g. [DOI] [PubMed] [Google Scholar]
  24. Moretta A., Vitale M., Sivori S., Bottino C., Morelli L., Augugliaro R., Barbaresi M., Pende D., Ciccone E., Lopez-Botet M. Human natural killer cell receptors for HLA-class I molecules. Evidence that the Kp43 (CD94) molecule functions as receptor for HLA-B alleles. J Exp Med. 1994 Aug 1;180(2):545–555. doi: 10.1084/jem.180.2.545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nakane A., Minagawa T., Kohanawa M., Chen Y., Sato H., Moriyama M., Tsuruoka N. Interactions between endogenous gamma interferon and tumor necrosis factor in host resistance against primary and secondary Listeria monocytogenes infections. Infect Immun. 1989 Nov;57(11):3331–3337. doi: 10.1128/iai.57.11.3331-3337.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nishimura H., Emoto M., Hiromatsu K., Yamamoto S., Matsuura K., Gomi H., Ikeda T., Itohara S., Yoshikai Y. The role of gamma delta T cells in priming macrophages to produce tumor necrosis factor-alpha. Eur J Immunol. 1995 May;25(5):1465–1468. doi: 10.1002/eji.1830250551. [DOI] [PubMed] [Google Scholar]
  27. Petrini J. H., Carroll A. M., Bosma M. J. T-cell receptor gene rearrangements in functional T-cell clones from severe combined immune deficient (scid) mice: reversion of the scid phenotype in individual lymphocyte progenitors. Proc Natl Acad Sci U S A. 1990 May;87(9):3450–3453. doi: 10.1073/pnas.87.9.3450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Skeen M. J., Ziegler H. K. 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. doi: 10.1084/jem.178.3.971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Spitalny G. L., Havell E. A. Monoclonal antibody to murine gamma interferon inhibits lymphokine-induced antiviral and macrophage tumoricidal activities. J Exp Med. 1984 May 1;159(5):1560–1565. doi: 10.1084/jem.159.5.1560. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES