Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1987 Nov 1;166(5):1536–1547. doi: 10.1084/jem.166.5.1536

Resistance of cytotoxic T lymphocytes to the lytic effects of their toxic granules

PMCID: PMC2189668  PMID: 2445890

Abstract

A cytotoxic T lymphocyte (CTL) characteristically kills target cells one after the other by releasing toxic granules that contain one or more cytolytic components. To determine how CTLs avoid destroying themselves when they release granules and lyse target cells, 7 murine CD8+ CTL cell lines were compared with 19 other cell lines for susceptibility to lysis by the isolated toxic granules. Murine CD8+ CTLs were clearly the most resistant cells: granules did not lyse them even after they were exposed to azide, cyanide, and 2-deoxyglucose, conditions that were found to enhance the susceptibility of all the other cells tested, including other T cells. Thus, resistance of CD8+ CTLs to cytotoxic granules appears to be independent of cellular ATP. To reconcile these findings with other observations that, under some circumstances, CTLs can be lysed by other CTLs, we suggest a model in which a CTL releases only a limited proportion of its toxic granules at each antigen-specific encounter with a target cell; the amount released is sufficient to kill most target cells but to leave the CTL undamaged and with enough granules to attack other target cells.

Full Text

The Full Text of this article is available as a PDF (764.4 KB).

Selected References

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

  1. Adams D. O., Hamilton T. A. The cell biology of macrophage activation. Annu Rev Immunol. 1984;2:283–318. doi: 10.1146/annurev.iy.02.040184.001435. [DOI] [PubMed] [Google Scholar]
  2. Baker P. E., Gillis S., Smith K. A. Monoclonal cytolytic T-cell lines. J Exp Med. 1979 Jan 1;149(1):273–278. doi: 10.1084/jem.149.1.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berke G., Sullivan K. A., Amos D. B. Tumor immunity in vitro: destruction of a mouse ascites tumor through a cycling pathway. Science. 1972 Aug 4;177(4047):433–434. doi: 10.1126/science.177.4047.433. [DOI] [PubMed] [Google Scholar]
  4. Borregaard N., Heiple J. M., Simons E. R., Clark R. A. Subcellular localization of the b-cytochrome component of the human neutrophil microbicidal oxidase: translocation during activation. J Cell Biol. 1983 Jul;97(1):52–61. doi: 10.1083/jcb.97.1.52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carney D. F., Hammer C. H., Shin M. L. Elimination of terminal complement complexes in the plasma membrane of nucleated cells: influence of extracellular Ca2+ and association with cellular Ca2+. J Immunol. 1986 Jul 1;137(1):263–270. [PubMed] [Google Scholar]
  6. Henkart P. A. Mechanism of lymphocyte-mediated cytotoxicity. Annu Rev Immunol. 1985;3:31–58. doi: 10.1146/annurev.iy.03.040185.000335. [DOI] [PubMed] [Google Scholar]
  7. Henkart P. A., Millard P. J., Reynolds C. W., Henkart M. P. Cytolytic activity of purified cytoplasmic granules from cytotoxic rat large granular lymphocyte tumors. J Exp Med. 1984 Jul 1;160(1):75–93. doi: 10.1084/jem.160.1.75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Herrmann S. H., Mescher M. F. Purification of the H-2Kk molecule of the murine major histocompatibility complex. J Biol Chem. 1979 Sep 25;254(18):8713–8716. [PubMed] [Google Scholar]
  9. Kearney J. F., Radbruch A., Liesegang B., Rajewsky K. A new mouse myeloma cell line that has lost immunoglobulin expression but permits the construction of antibody-secreting hybrid cell lines. J Immunol. 1979 Oct;123(4):1548–1550. [PubMed] [Google Scholar]
  10. Koren H. S., Ax W., Freund-Moelbert E. Morphological observations on the contact-induced lysis of target cells. Eur J Immunol. 1973 Jan;3(1):32–37. doi: 10.1002/eji.1830030108. [DOI] [PubMed] [Google Scholar]
  11. Kranz D. M., Eisen H. N. Resistance of cytotoxic T lymphocytes to lysis by a clone of cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1987 May;84(10):3375–3379. doi: 10.1073/pnas.84.10.3375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kuppers R. C., Henney C. S. Evidence for direct linkage between antigen recognition and lytic expression in effector T cells. J Exp Med. 1976 Mar 1;143(3):684–689. doi: 10.1084/jem.143.3.684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Luciani M. F., Brunet J. F., Suzan M., Denizot F., Golstein P. Self-sparing of long-term in vitro-cloned or uncloned cytotoxic T lymphocytes. J Exp Med. 1986 Sep 1;164(3):962–967. doi: 10.1084/jem.164.3.962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Masson D., Nabholz M., Estrade C., Tschopp J. Granules of cytolytic T-lymphocytes contain two serine esterases. EMBO J. 1986 Jul;5(7):1595–1600. doi: 10.1002/j.1460-2075.1986.tb04401.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Masson D., Tschopp J. Isolation of a lytic, pore-forming protein (perforin) from cytolytic T-lymphocytes. J Biol Chem. 1985 Aug 5;260(16):9069–9072. [PubMed] [Google Scholar]
  16. Nakamura M., Ross D. T., Briner T. J., Gefter M. L. Cytolytic activity of antigen-specific T cells with helper phenotype. J Immunol. 1986 Jan;136(1):44–47. [PubMed] [Google Scholar]
  17. Nathan C., Cohn Z. Role of oxygen-dependent mechanisms in antibody-induced lysis of tumor cells by activated macrophages. J Exp Med. 1980 Jul 1;152(1):198–208. doi: 10.1084/jem.152.1.198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pasternack M. S., Verret C. R., Liu M. A., Eisen H. N. Serine esterase in cytolytic T lymphocytes. Nature. 1986 Aug 21;322(6081):740–743. doi: 10.1038/322740a0. [DOI] [PubMed] [Google Scholar]
  19. Podack E. R., Konigsberg P. J. Cytolytic T cell granules. Isolation, structural, biochemical, and functional characterization. J Exp Med. 1984 Sep 1;160(3):695–710. doi: 10.1084/jem.160.3.695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Podack E. R. Molecular mechanisms of cytolysis by complement and by cytolytic lymphocytes. J Cell Biochem. 1986;30(2):133–170. doi: 10.1002/jcb.240300205. [DOI] [PubMed] [Google Scholar]
  21. Ramm L. E., Whitlow M. B., Koski C. L., Shin M. L., Mayer M. M. Elimination of complement channels from the plasma membranes of U937, a nucleated mammalian cell line: temperature dependence of the elimination rate. J Immunol. 1983 Sep;131(3):1411–1415. [PubMed] [Google Scholar]
  22. Reilly E. B., Kranz D. M., Tonegawa S., Eisen H. N. A functional gamma gene formed from known gamma-gene segments is not necessary for antigen-specific responses of murine cytotoxic T lymphocytes. 1986 Jun 26-Jul 2Nature. 321(6073):878–880. doi: 10.1038/321878a0. [DOI] [PubMed] [Google Scholar]
  23. Russell J. H., Masakowski V., Rucinsky T., Phillips G. Mechanisms of immune lysis. III. Characterization of the nature and kinetics of the cytotoxic T lymphocyte-induced nuclear lesion in the target. J Immunol. 1982 May;128(5):2087–2094. [PubMed] [Google Scholar]
  24. Sitkovsky M. V., Pasternack M. S., Eisen H. N. Inhibition of cytotoxic T lymphocyte activity by concanavalin A. J Immunol. 1982 Oct;129(4):1372–1376. [PubMed] [Google Scholar]
  25. Tirosh R., Berke G. T-Lymphocyte-mediated cytolysis as an excitatory process of the target. I. Evidence that the target cell may be the site of Ca2+ action. Cell Immunol. 1985 Oct 1;95(1):113–123. doi: 10.1016/0008-8749(85)90300-4. [DOI] [PubMed] [Google Scholar]
  26. Tite J. P., Janeway C. A., Jr Cloned helper T cells can kill B lymphoma cells in the presence of specific antigen: Ia restriction and cognate vs. noncognate interactions in cytolysis. Eur J Immunol. 1984 Oct;14(10):878–886. doi: 10.1002/eji.1830141004. [DOI] [PubMed] [Google Scholar]
  27. Tite J. P., Powell M. B., Ruddle N. H. Protein-antigen specific Ia-restricted cytolytic T cells: analysis of frequency, target cell susceptibility, and mechanism of cytolysis. J Immunol. 1985 Jul;135(1):25–33. [PubMed] [Google Scholar]
  28. Young J. D., Hengartner H., Podack E. R., Cohn Z. A. Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer activity. Cell. 1986 Mar 28;44(6):849–859. doi: 10.1016/0092-8674(86)90007-3. [DOI] [PubMed] [Google Scholar]
  29. Young J. D., Leong L. G., Liu C. C., Damiano A., Wall D. A., Cohn Z. A. Isolation and characterization of a serine esterase from cytolytic T cell granules. Cell. 1986 Oct 24;47(2):183–194. doi: 10.1016/0092-8674(86)90441-1. [DOI] [PubMed] [Google Scholar]

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

RESOURCES