Serine protease inhibitor 6 protects iNKT cells from self-inflicted damage.
The role played by apoptosis in the homeostasis of effector cells of the innate immune system is unclear. Serine protease inhibitor 6 (Spi6) is an inhibitor of granzyme B (GrB) that protects cytotoxic T lymphocytes of the adaptive immune system from apoptosis. To determine whether Spi6 also protects cells of the innate immune system from self-inflicted damage we have examined invariant NKT (iNKT) cells. Spi6-deficient iNKT cells harbored increased levels of GrB after TCR stimulation with the PBS-57 glycolipid Ag and were susceptible to apoptosis. The increased apoptosis of Spi6 knock-out (KO) iNKT cells lead to a complete loss in the production of IL-4 and IFN-gamma by Spi6 KO iNKT cells after PBS-57 challenge. The increased activation-induced apoptosis resulted in impaired survival and a decreased clonal burst size of Spi6 KO iNKT cells, which could be corrected by GrB deficiency. However, the clonal burst of Spi6 KO iNKT cells after TCR-independent activation with lymphocytic choriomeningitis virus was not affected. Our findings demonstrate that Spi6 protects cytotoxic cells of the innate immune system from GrB-mediated self-inflicted triggered by the recognition of Ag.
Ansari
A Wahid
AW
Section of Immunobiology, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London, United Kingdom.
Temblay
Jeff N
JN
Alyahya
Syarifah H
SH
Ashton-Rickardt
Philip G
PG
D000818:Animals; D017209:Apoptosis; D001117:Arenaviridae Infections / Q000276:immunology; D049109:Cell Proliferation; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008088:Listeriosis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D008565:Membrane Proteins; D015843:Serpins; D015847:Interleukin-4; D007371:Interferon-gamma; D053804:Granzymes; D012697:Serine Endopeptidases; C106610:Serpinb9 protein, mouse