Serine protease inhibitor 6 protects cytotoxic T cells from self-inflicted injury by ensuring the integrity of cytotoxic granules

Immunity. 2006 Apr;24(4):451-61. doi: 10.1016/j.immuni.2006.02.002.


How cytotoxic T lymphocytes (CTLs) kill intracellular pathogens without killing themselves has been a recurring question ever since their discovery. By using mice deficient in Serine Protease Inhibitor 6 (Spi6), we show that by inhibiting granzyme B (GrB), Spi6 protects CTLs from self-inflicted injury. Infection with either Lymphocytic Choriomeningitis virus (LCMV) or Listeria monocytogenes (LM) revealed increased apoptosis and diminished survival of Spi6 knockout (KO) CTLs, which was cell autonomous and could be corrected by GrB deficiency. Spi6 KO mice in turn were impaired in their ability to clear LCMV infection. Spi6 KO CTLs revealed a breakdown in the integrity of cytotoxic granules, increased cytoplasmic GrB, and ensuing apoptosis. We conclude that Spi6 protects CTLs from suicide caused by GrB-mediated breakdown of cytotoxic granules.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arenaviridae Infections / immunology
  • Blotting, Western
  • Cytoplasmic Granules / immunology
  • Cytoplasmic Granules / metabolism*
  • Cytotoxicity, Immunologic
  • Flow Cytometry
  • Granzymes
  • Listeriosis / immunology
  • Lymphocytic choriomeningitis virus / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine Endopeptidases / immunology
  • Serine Endopeptidases / metabolism*
  • Serpins / metabolism*
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism


  • Membrane Proteins
  • Serpins
  • Granzymes
  • Gzmb protein, mouse
  • Serine Endopeptidases
  • Serpinb9 protein, mouse