Serine Protease Inhibitor 6 Protects Cytotoxic T Cells from Self-Inflicted Injury by Ensuring the Integrity of Cytotoxic Granules

Manling Zhang, Sun Mi Park, Yue Wang, Ramila Shah, Ni Liu, Andrea E. Murmann, Chyung Ru Wang, Marcus E. Peter, Philip G. Ashton-Rickardt*

*Corresponding author for this work

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)451-461
Number of pages11
JournalImmunity
Volume24
Issue number4
DOIs
StatePublished - Apr 1 2006

Keywords

  • CELLIMMUNO
  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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