Serine protease inhibitor 6 protects cytotoxic T cells from self-inflicted injury by ensuring the integrity of cytotoxic granules.
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.
Zhang
Manling
M
Department of Pathology, The University of Chicago, 924 East 57th Street, Illinois 60637, USA.
Park
Sun-Mi
SM
Wang
Yue
Y
Shah
Ramila
R
Liu
Ni
N
Murmann
Andrea E
AE
Wang
Chyung-Ru
CR
Peter
Marcus E
ME
Ashton-Rickardt
Philip G
PG
D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology; D015153:Blotting, Western; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D053804:Granzymes; D008088:Listeriosis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism*; D015843:Serpins / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
D008565:Membrane Proteins; D015843:Serpins; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; C106610:Serpinb9 protein, mouse