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* Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia;
Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra City, Australia;
Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia; and
Department of Pathology, Ben May Institute for Cancer Research and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637
Granzyme B (grB) is a serine proteinase released by cytotoxic
lymphocytes (CLs) to kill abnormal cells. GrB-mediated apoptotic
pathways are conserved in nucleated cells; hence, CLs require
mechanisms to protect against ectopic or misdirected grB. The
nucleocytoplasmic serpin, proteinase inhibitor 9 (PI-9), is a potent
inhibitor of grB that protects cells from grB-mediated apoptosis in
model systems. Here we show that PI-9 is present in CD4+
cells, CD8+ T cells, NK cells, and at lower levels in B
cells and myeloid cells. PI-9 is up-regulated in response to grB
production and degranulation, and associates with grB-containing
granules in activated CTLs and NK cells. Intracellular complexes of
PI-9 and grB are evident in NK cells, and overexpression of PI-9
enhances CTL potency, suggesting that cytoplasmic grB, which may
threaten CL viability, is rapidly inactivated by PI-9. Because
dendritic cells (DCs) acquire characteristics similar to those of
target cells to activate naive CD8+ T cells and therefore
may also require protection against grB, we investigated the expression
of PI-9 in DCs. PI-9 is evident in thymic DCs (CD3-,
CD4+, CD8-, CD45+), tonsillar DCs,
and DC subsets purified from peripheral blood (CD16+
monocytes and CD123+ plasmacytoid DCs). Furthermore, PI-9
is expressed in monocyte-derived DCs and is up-regulated upon
TNF-
-induced maturation of monocyte-derived DCs. In conclusion, the
presence and subcellular localization of PI-9 in leukocytes and DCs are
consistent with a protective role against ectopic or misdirected grB
during an immune response.
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