Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1991 Oct 1;174(4):755–759. doi: 10.1084/jem.174.4.755

Antileishmanial defense in macrophages triggered by tumor necrosis factor expressed on CD4+ T lymphocyte plasma membrane

PMCID: PMC2118977  PMID: 1680956

Abstract

In our studies of host defense to the intracellular protozoan Leishmania major, we uncovered a novel mechanism of antileishmanial defense that involves direct cell contact between effector CD4+ lymphocytes and Leishmania-infected macrophages. The mechanism is distinctive because it does not involve lymphokine secretion and induces no cytotoxic effects in the host cells; its expression is antigen-specific and genetically restricted. We now demonstrate that these effector CD4+ cells display tumor necrosis factor (TNF) on their surface and provide evidence that the membrane-associated TNF is involved in the activation of the antileishmanial defense. Using a Leishmania-specific cloned T-T cell hybridoma line (1B6; CD4+, T helper type 1) that activates antileishmanial defense in macrophages through cell contact and does not secrete TNF, we noted that only cells bearing surface TNF (TNF+), but not ones lacking surface TNF (TNF-), exerted these effects. Moreover, the antileishmanial effects excreted by TNF+ 1B6 cells as well as by lymph node CD4+ TNF+ lymphocytes could be blocked with anti-TNF antibody. We propose that membrane-associated TNF on CD4+ T cells may provide a mechanism of targeting activation signals to macrophages in an antigen-specific and genetically restricted manner.

Full Text

The Full Text of this article is available as a PDF (566.3 KB).

Selected References

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

  1. Beutler B., Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. doi: 10.1146/annurev.iy.07.040189.003205. [DOI] [PubMed] [Google Scholar]
  2. Blake M. S., Johnston K. H., Russell-Jones G. J., Gotschlich E. C. A rapid, sensitive method for detection of alkaline phosphatase-conjugated anti-antibody on Western blots. Anal Biochem. 1984 Jan;136(1):175–179. doi: 10.1016/0003-2697(84)90320-8. [DOI] [PubMed] [Google Scholar]
  3. De Titto E. H., Catterall J. R., Remington J. S. Activity of recombinant tumor necrosis factor on Toxoplasma gondii and Trypanosoma cruzi. J Immunol. 1986 Aug 15;137(4):1342–1345. [PubMed] [Google Scholar]
  4. Flick D. A., Gifford G. E. Comparison of in vitro cell cytotoxic assays for tumor necrosis factor. J Immunol Methods. 1984 Mar 30;68(1-2):167–175. doi: 10.1016/0022-1759(84)90147-9. [DOI] [PubMed] [Google Scholar]
  5. Fowles R. E., Fajardo I. M., Leibowitch J. L., David J. R. The enhancement of macrophage bacteriostasis by products of activated lymphocytes. J Exp Med. 1973 Oct 1;138(4):952–964. doi: 10.1084/jem.138.4.952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hämmerling G. J. T lymphocyte tissue culture lines produced by cell hybridization. Eur J Immunol. 1977 Oct;7(10):743–746. doi: 10.1002/eji.1830071018. [DOI] [PubMed] [Google Scholar]
  7. Kinkhabwala M., Sehajpal P., Skolnik E., Smith D., Sharma V. K., Vlassara H., Cerami A., Suthanthiran M. A novel addition to the T cell repertory. Cell surface expression of tumor necrosis factor/cachectin by activated normal human T cells. J Exp Med. 1990 Mar 1;171(3):941–946. doi: 10.1084/jem.171.3.941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kriegler M., Perez C., DeFay K., Albert I., Lu S. D. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell. 1988 Apr 8;53(1):45–53. doi: 10.1016/0092-8674(88)90486-2. [DOI] [PubMed] [Google Scholar]
  9. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  10. Liew F. Y., Parkinson C., Millott S., Severn A., Carrier M. Tumour necrosis factor (TNF alpha) in leishmaniasis. I. TNF alpha mediates host protection against cutaneous leishmaniasis. Immunology. 1990 Apr;69(4):570–573. [PMC free article] [PubMed] [Google Scholar]
  11. Liu C. C., Detmers P. A., Jiang S. B., Young J. D. Identification and characterization of a membrane-bound cytotoxin of murine cytolytic lymphocytes that is related to tumor necrosis factor/cachectin. Proc Natl Acad Sci U S A. 1989 May;86(9):3286–3290. doi: 10.1073/pnas.86.9.3286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Luettig B., Decker T., Lohmann-Matthes M. L. Evidence for the existence of two forms of membrane tumor necrosis factor: an integral protein and a molecule attached to its receptor. J Immunol. 1989 Dec 15;143(12):4034–4038. [PubMed] [Google Scholar]
  13. Mackaness G. B. The influence of immunologically committed lymphoid cells on macrophage activity in vivo. J Exp Med. 1969 May 1;129(5):973–992. doi: 10.1084/jem.129.5.973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Nacy C. A., Oster C. N., James S. L., Meltzer M. S. Activation of macrophages to kill rickettsiae and Leishmania: dissociation of intracellular microbicidal activities and extracellular destruction of neoplastic and helminth targets. Contemp Top Immunobiol. 1984;13:147–170. doi: 10.1007/978-1-4757-1445-6_8. [DOI] [PubMed] [Google Scholar]
  15. Neva F. A., Wyler D., Nash T. Cutaneous leishmaniasis--a case with persistent organisms after treatment in presence of normal immune response. Am J Trop Med Hyg. 1979 May;28(3):467–471. [PubMed] [Google Scholar]
  16. Panosian C. B., Sypek J. P., Wyler D. J. Cell contact-mediated macrophage activation for antileishmanial defense. I. Lymphocyte effector mechanism that is contact dependent and noncytotoxic. J Immunol. 1984 Dec;133(6):3358–3365. [PubMed] [Google Scholar]
  17. Sheehan K. C., Ruddle N. H., Schreiber R. D. Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors. J Immunol. 1989 Jun 1;142(11):3884–3893. [PubMed] [Google Scholar]
  18. Simon H. B., Sheagren J. N. Cellular immunity in vitro. I. Immunologically mediated enhancement of macrophage bactericidal capacity. J Exp Med. 1971 Jun 1;133(6):1377–1389. doi: 10.1084/jem.133.6.1377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Simon H. B., Sheagren J. N. Enhancement of macrophage bactericidal capacity by antigenically stimulated immune lymphocytes. Cell Immunol. 1972 Jun;4(2):163–174. doi: 10.1016/0008-8749(72)90015-9. [DOI] [PubMed] [Google Scholar]
  20. Sypek J. P., Matzilevich M. M., Wyler D. J. Th2 lymphocyte clone can activate macrophage antileishmanial defense by a lymphokine-independent mechanism in vitro and can augment parasite attrition in vivo. Cell Immunol. 1991 Mar;133(1):178–186. doi: 10.1016/0008-8749(91)90189-i. [DOI] [PubMed] [Google Scholar]
  21. Sypek J. P., Panosian C. B., Wyler D. J. Antigen recognition by effector T cells in antileishmanial defense. J Infect Dis. 1985 Nov;152(5):1057–1063. doi: 10.1093/infdis/152.5.1057. [DOI] [PubMed] [Google Scholar]
  22. Sypek J. P., Panosian C. B., Wyler D. J. Cell contact-mediated macrophage activation for antileishmanial defense. II. Identification of effector cell phenotype and genetic restriction. J Immunol. 1984 Dec;133(6):3351–3357. [PubMed] [Google Scholar]
  23. Sypek J. P., Wyler D. J. Cell contact-mediated macrophage activation for antileishmanial defence: mapping of the genetic restriction to the I region of the MHC. Clin Exp Immunol. 1985 Dec;62(3):449–457. [PMC free article] [PubMed] [Google Scholar]
  24. Sypek J. P., Wyler D. J. Susceptibility of lymphokine-resistant Leishmania to cell contact-mediated macrophage activation. J Infect Dis. 1988 Aug;158(2):392–397. doi: 10.1093/infdis/158.2.392. [DOI] [PubMed] [Google Scholar]
  25. Sypek J. P., Wyler D. J. T-cell hybridomas reveal two distinct mechanisms of antileishmanial defense. Infect Immun. 1990 May;58(5):1146–1152. doi: 10.1128/iai.58.5.1146-1152.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wyler D. J., Beller D. I., Sypek J. P. Macrophage activation for antileishmanial defense by an apparently novel mechanism. J Immunol. 1987 Feb 15;138(4):1246–1249. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES