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

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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 ≥ 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 LeuLeu-OMe and may provide a target for the development of other immunotherapeutic agents designed to delete cytotoxic lymphocyte responses.

Original languageEnglish (US)
Pages (from-to)83-87
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume87
Issue number1
Publication statusPublished - 1990

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Keywords

  • Cytotoxic T lymphocytes
  • Immunosuppressive agents
  • Natural killer cells

ASJC Scopus subject areas

  • Genetics
  • General

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