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A null mutation in the perforin gene impairs cytolytic T lymphocyte- and natural killer cell-mediated cytotoxicity

B Lowin1, F Beermann, A Schmidt

  • 1Institute of Biochemistry, University of Lausanne, Switzerland.

Proceedings of the National Academy of Sciences of the United States of America
|November 22, 1994
PubMed

Insights

Perforin is crucial for lymphocyte-mediated cytotoxicity, but not the sole mechanism. Mice lacking perforin show impaired, yet not abolished, T cell and NK cell killing activity, indicating alternative pathways exist.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Genetics

Background:

  • Lymphocyte-mediated cytotoxicity is primarily attributed to perforin secretion.
  • Perforin-independent cytotoxic pathways have been proposed but not fully elucidated.

Purpose of the Study:

  • To investigate the essential role of perforin in lymphocyte-mediated cytotoxicity.
  • To determine if perforin-deficient lymphocytes retain cytolytic function.

Main Methods:

  • Gene targeting in embryonic stem cells to create perforin-deficient mice.
  • Analysis of T cell and Natural Killer (NK) cell activation, granzyme A secretion, and killing activity.
  • Assessment of target cell lysis and apoptotic cell death.

Main Results:

  • Perforin-deficient mice lack perforin mRNA and are phenotypically healthy.
  • T cell and NK cell activation and granzyme A secretion are unaffected.
  • Cytolytic activity of T cells and NK cells is significantly impaired but approximately one-third remains.

Conclusions:

  • Perforin is a critical effector molecule for T cell- and NK cell-mediated cytolysis.
  • Alternative, perforin-independent mechanisms contribute to lymphocyte-mediated killing.

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