Serine protease inhibitor 6 is required to protect dendritic cells from the kiss of death.
How dendritic cells (DC) present Ag to cytotoxic T cells (CTL) without themselves being killed through contact-mediated cytotoxicity (so-called kiss of death) has proved to be controversial. Using mice deficient in serine protease inhibitor 6 (Spi6), we show that Spi6 protects DC from the kiss of death by inhibiting granzyme B (GrB) delivered by CTL. Infection of Spi6 knockout mice with lymphocytic choriomeningitis virus revealed impaired survival of CD8α DC. The impaired survival of Spi6 knockout CD8α DC resulted in impaired priming and expansion of both primary and memory lymphocytic choriomeningitis virus-specific CTL, which could be corrected by GrB deficiency. The rescue in the clonal burst obtained by GrB elimination demonstrated that GrB was the physiological target through which Spi6 protected DC from CTL. We conclude that the negative regulation of DC priming of CD8 T lymphocyte immunity by CTL killing is mitigated by the physiological inhibition of GrB by Spi6.
Section of Immunobiology, Division of Immunology and Inflammation, Department of Medicine, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom.
Elena
E
Lovo
Manling
M
Zhang
Lihui
L
Wang
Philip G
PG
Ashton-Rickardt
D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D053804:Granzymes / Q000276:immunology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012697:Serine Endopeptidases / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000502:physiology; D015843:Serpins / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D008565:Membrane Proteins; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D053804:Granzymes; D012697:Serine Endopeptidases; C106610:Serpinb9 protein, mouse