Tumor necrosis factor and lymphotoxin secretion by human natural killer cells leads to antiviral cytotoxicity

C V Paya1, N Kenmotsu, R A Schoon

  • 1Department of Immunology, Mayo Clinic and Foundation, Rochester, MN 55905.

Insights

Natural killer (NK) cells combat viral infections by secreting tumor necrosis factor (TNF) and lymphotoxin. These proteins selectively kill virus-infected cells, contributing to antiviral immunity.

Area of Science:

  • Immunology
  • Virology
  • Cell Biology

Background:

  • Natural killer (NK) cells are crucial for innate immunity, primarily known for their role in tumor cell cytotoxicity.
  • The specific mechanisms by which NK cells mediate antiviral immunity are not fully elucidated.

Purpose of the Study:

  • To investigate the role of specific proteins secreted by NK cells in antiviral immunity.
  • To identify the soluble factors responsible for NK cell-mediated killing of virally infected cells.

Main Methods:

  • Human CD16+/CD3- NK cells were isolated using fluorescence-activated cell sorting (FACS) and cloned via limiting dilution.
  • NK cell supernatants were tested for antiviral activity against vesicular stomatitis virus (VSV)-infected cells.
  • The effect of antibodies against tumor necrosis factor (TNF) and lymphotoxin on antiviral activity was assessed.
  • Recombinant human TNF was used to confirm its cytotoxic effects on various virus-infected cells.

Main Results:

  • NK cell lines exhibited cytotoxicity against both tumor and virally infected cells.
  • NK cell supernatants selectively killed VSV-infected cells while sparing uninfected cells.
  • This soluble antiviral activity was neutralized by antibodies against TNF and lymphotoxin.
  • Recombinant TNF demonstrated specific cytotoxicity against VSV, CMV, Theiler's murine encephalomyelitis virus, and HSV-infected cells, with variations depending on the virus and cell type.

Conclusions:

  • NK cells can mediate direct and selective cytotoxicity against virally infected cells.
  • Tumor necrosis factor (TNF) and lymphotoxin are key secreted proteins responsible for this NK cell-mediated antiviral effect.

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