Perforin and Granzymes Have Distinct Roles in Defensive Immunity and Immunopathology

S. L H van Dommelen, Nital Sumaria, Robert D. Schreiber, Anthony A Scalzo, Mark J. Smyth, Mariapia A. Degli-Esposti

Research output: Contribution to journalArticleResearchpeer-review

109 Citations (Scopus)

Abstract

Successful control of viral infection requires the host to eliminate the infecting pathogen without causing overt immunopathology. Here we showed that perforin (Prf1) and granzymes (Gzms) have distinct roles in defensive immunity and immunopathology in a well-established model of viral infection. Both Prf1 and Gzms drastically affected the outcome of murine cytomegalovirus (MCMV) infection. Viral titres increased markedly in both Prf1-/- and Gzma-/-Gzmb-/- mice, but Gzma-/-Gzmb-/- mice recovered and survived infection, whereas Prf1-/- mice did not. Indeed, infected Prf1-deficient hosts developed a fatal hemophagocytic lymphohistiocytosis (HLH)-like syndrome. This distinction in outcome depended on accumulation of mononuclear cells and T cells in infected Prf1-/- mice. Importantly, blocking experiments that clearly identified tumor necrosis factor-α (TNF-α) as the principal contributor to the lethality observed in infected Prf1-/- mice provided support for the clinical potential of such an approach in HLH patients whose disease is triggered by viral infection.

Original languageEnglish
Pages (from-to)835-848
Number of pages14
JournalImmunity
Volume25
Issue number5
DOIs
Publication statusPublished - 1 Nov 2006
Externally publishedYes

Keywords

  • CELLIMMUNO
  • MICROBIO

Cite this