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. 1990 Jan;87(1):83–87. doi: 10.1073/pnas.87.1.83

Mechanism of L-leucyl-L-leucine methyl ester-mediated killing of cytotoxic lymphocytes: dependence on a lysosomal thiol protease, dipeptidyl peptidase I, that is enriched in these cells.

D L Thiele 1, P E Lipsky 1
PMCID: PMC53204  PMID: 2296607

Abstract

Exposure of murine or human lymphocytes to L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) results in selective killing of cytotoxic lymphocytes, whereas helper T cells and B cells remain functionally intact. Cytolytic lymphocytes incubated in the presence of toxic concentrations of Leu-Leu-OMe were found to contain membranolytic metabolites of the structure (Leu-Leu)n-OMe, where n greater than or equal to 3. The sensitivity of cytotoxic lymphocytes to Leu-Leu-OMe was found to be dependent upon production of these metabolites by a lysosomal thiol protease, dipeptidyl peptidase I, which is present at far higher levels in cytotoxic lymphocytes than in cells without cytolytic potential or not of bone marrow origin. Thus, this granule enzyme is required for the unique effects of Leu-Leu-OMe and may provide a target for the development of other immunotherapeutic agents designed to delete cytotoxic lymphocyte responses.

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Selected References

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

  1. Barrett A. J., Kirschke H. Cathepsin B, Cathepsin H, and cathepsin L. Methods Enzymol. 1981;80(Pt 100):535–561. doi: 10.1016/s0076-6879(81)80043-2. [DOI] [PubMed] [Google Scholar]
  2. Charley M., Thiele D. L., Bennett M., Lipsky P. E. Prevention of lethal murine graft versus host disease by treatment of donor cells with L-leucyl-L-leucine methyl ester. J Clin Invest. 1986 Nov;78(5):1415–1420. doi: 10.1172/JCI112730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Gelman B. B., Papa L., Davis M. H., Gruenstein E. Decreased lysosomal dipeptidyl aminopeptidase I activity in cultured human skin fibroblasts in Duchenne's muscular dystrophy. J Clin Invest. 1980 Jun;65(6):1398–1406. doi: 10.1172/JCI109804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gershenfeld H. K., Weissman I. L. Cloning of a cDNA for a T cell-specific serine protease from a cytotoxic T lymphocyte. Science. 1986 May 16;232(4752):854–858. doi: 10.1126/science.2422755. [DOI] [PubMed] [Google Scholar]
  5. Goldman R., Kaplan A. Rupture of rat liver lysosomes mediated by L-amino acid esters. Biochim Biophys Acta. 1973 Aug 22;318(2):205–216. doi: 10.1016/0005-2736(73)90114-4. [DOI] [PubMed] [Google Scholar]
  6. Green G. D., Shaw E. Peptidyl diazomethyl ketones are specific inactivators of thiol proteinases. J Biol Chem. 1981 Feb 25;256(4):1923–1928. [PubMed] [Google Scholar]
  7. Kranz D. M., Pasternack M. S., Eisen H. N. Recognition and lysis of target cells by cytotoxic T lymphocytes. Fed Proc. 1987 Feb;46(2):309–312. [PubMed] [Google Scholar]
  8. Lanier L. L., Phillips J. H., Hackett J., Jr, Tutt M., Kumar V. Natural killer cells: definition of a cell type rather than a function. J Immunol. 1986 Nov 1;137(9):2735–2739. [PubMed] [Google Scholar]
  9. Liu C. C., Steffen M., King F., Young J. D. Identification, isolation, and characterization of a novel cytotoxin in murine cytolytic lymphocytes. Cell. 1987 Nov 6;51(3):393–403. doi: 10.1016/0092-8674(87)90635-0. [DOI] [PubMed] [Google Scholar]
  10. Lobe C. G., Finlay B. B., Paranchych W., Paetkau V. H., Bleackley R. C. Novel serine proteases encoded by two cytotoxic T lymphocyte-specific genes. Science. 1986 May 16;232(4752):858–861. doi: 10.1126/science.3518058. [DOI] [PubMed] [Google Scholar]
  11. Masson D., Tschopp J. A family of serine esterases in lytic granules of cytolytic T lymphocytes. Cell. 1987 Jun 5;49(5):679–685. doi: 10.1016/0092-8674(87)90544-7. [DOI] [PubMed] [Google Scholar]
  12. Miller D. K., Griffiths E., Lenard J., Firestone R. A. Cell killing by lysosomotropic detergents. J Cell Biol. 1983 Dec;97(6):1841–1851. doi: 10.1083/jcb.97.6.1841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Pasternack M. S., Eisen H. N. A novel serine esterase expressed by cytotoxic T lymphocytes. 1985 Apr 25-May 1Nature. 314(6013):743–745. doi: 10.1038/314743a0. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Smith P. K., Krohn R. I., Hermanson G. T., Mallia A. K., Gartner F. H., Provenzano M. D., Fujimoto E. K., Goeke N. M., Olson B. J., Klenk D. C. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985 Oct;150(1):76–85. doi: 10.1016/0003-2697(85)90442-7. [DOI] [PubMed] [Google Scholar]
  17. Thiele D. L., Bryde S. E., Lipsky P. E. Lethal graft-vs-host disease induced by a class II MHC antigen only disparity is not mediated by cytotoxic T cells. J Immunol. 1988 Nov 15;141(10):3377–3382. [PubMed] [Google Scholar]
  18. Thiele D. L., Charley M. R., Calomeni J. A., Lipsky P. E. Lethal graft-vs-host disease across major histocompatibility barriers: requirement for leucyl-leucine methyl ester sensitive cytotoxic T cells. J Immunol. 1987 Jan 1;138(1):51–57. [PubMed] [Google Scholar]
  19. Thiele D. L., Lipsky P. E. Regulation of cellular function by products of lysosomal enzyme activity: elimination of human natural killer cells by a dipeptide methyl ester generated from L-leucine methyl ester by monocytes or polymorphonuclear leukocytes. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2468–2472. doi: 10.1073/pnas.82.8.2468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Thiele D. L., Lipsky P. E. The immunosuppressive activity of L-leucyl-L-leucine methyl ester: selective ablation of cytotoxic lymphocytes and monocytes. J Immunol. 1986 Feb 1;136(3):1038–1048. [PubMed] [Google Scholar]
  21. 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]
  22. Young J. D., Peterson C. G., Venge P., Cohn Z. A. Mechanism of membrane damage mediated by human eosinophil cationic protein. Nature. 1986 Jun 5;321(6070):613–616. doi: 10.1038/321613a0. [DOI] [PubMed] [Google Scholar]

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