The granzyme B-Serpinb9 axis controls the fate of lymphocytes after lysosomal stress

Bird, C. H., Christensen, M. E., Mangan, M. S. J., Prakash, M. D., Sedelies, K. A., Smyth, M. J., Harper, I., Waterhouse, N. J. and Bird, P. I. (2014) The granzyme B-Serpinb9 axis controls the fate of lymphocytes after lysosomal stress. Cell Death and Differentiation, 21 6: 876-887. doi:10.1038/cdd.2014.7

Author Bird, C. H.
Christensen, M. E.
Mangan, M. S. J.
Prakash, M. D.
Sedelies, K. A.
Smyth, M. J.
Harper, I.
Waterhouse, N. J.
Bird, P. I.
Title The granzyme B-Serpinb9 axis controls the fate of lymphocytes after lysosomal stress
Journal name Cell Death and Differentiation   Check publisher's open access policy
ISSN 1476-5403
Publication date 2014-01-01
Sub-type Article (original research)
DOI 10.1038/cdd.2014.7
Volume 21
Issue 6
Start page 876
End page 887
Total pages 12
Place of publication London, England, U.K.
Publisher Nature Publishing Group
Language eng
Subject 1307 Cell Biology
1312 Molecular Biology
2700 Medicine
Abstract Cytotoxic lymphocytes (CLs) contain lysosome-related organelles (LROs) that perform the normal degradative functions of the lysosome, in addition to storage and release of powerful cytotoxins employed to kill virally infected or abnormal cells. Among these cytotoxins is granzyme B (GrB), a protease that has also been implicated in activation (restimulation)-induced cell death of natural killer (NK) and T cells, but the underlying mechanism and its regulation are unclear. Here we show that restimulation of previously activated human or mouse lymphocytes induces lysosomal membrane permeabilisation (LMP), followed by GrB release from LROs into the CL cytosol. The model lysosomal stressors sphingosine and Leu-Leu-methyl-ester, and CLs from gene-targeted mice were used to show that LMP releases GrB in both a time-and concentration-dependent manner, and that the liberated GrB is responsible for cell death. The endogenous GrB inhibitor Serpinb9 (Sb9) protects CLs against LMP-induced death but is decreasingly effective as the extent of LMP increases. We also used these model stressors to show that GrB is the major effector of LMP-mediated death in T cells, but that in NK cells additional effectors are released, making GrB redundant. We found that limited LMP and GrB release occurs constitutively in proliferating lymphocytes and in NK cells engaged with targets in vitro. In Ectromelia virus-infected lymph nodes, working NK cells lacking Sb9 are more susceptible to GrB-mediated death. Taken together, these data show that a basal level of LMP occurs in proliferating and activated lymphocytes, and is increased on restimulation. LMP releases GrB from LROs into the lymphocyte cytoplasm and its ensuing interaction with Sb9 dictates whether or not the cell survives. The GrB-Sb9 nexus may therefore represent an additional mechanism of limiting lymphocyte lifespan and populations.
Keyword activation-induced cell death
cytotoxic lymphocytes
granzyme B
lysosomal membrane permeabilisation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 4 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 01 Apr 2015, 08:30:57 EST by Matthew Lamb on behalf of School of Medicine