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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 963-973
The 5' Flanking Region of the Human Granzyme H Gene Directs
Expression to T/Natural Killer Cell Progenitors and
Lymphokine-Activated Killer Cells in Transgenic Mice
Debra M. MacIvor,
Christine T.N. Pham, and
Timothy J. Ley
From the Departments of Internal Medicine and Genetics, Division of
Bone Marrow Transplantation and Stem Cell Biology, Washington
University Medical School, St Louis, MO.
Human granzyme H is a neutral serine protease that is expressed
predominantly in the lymphokine-activated killer (LAK)/natural killer
(NK) compartment of the immune system. The gene that encodes this
granzyme is located between the granzyme B and cathepsin G genes on
human chromosome 14q11.2. Although the murine orthologue of human
granzyme H has not yet been identified, murine granzymes C, D, E, F,
and G also lie between the murine granzyme B and cathepsin G genes on
murine chromosome 14; murine granzymes C, D, and F are also highly
expressed in LAK cells, but minimally in cytotoxic T lymphocytes (CTL).
We therefore tested whether the 5' flanking region of human
granzyme H contains the cis-acting DNA sequences necessary to target a
reporter gene to the LAK/NK compartment of transgenic mice. A 1.2-kb
fragment of 5' flanking human granzyme H sequence was linked to
an SV40 large T-antigen (TAg) reporter gene and used to create six
transgenic founder lines. SV40 TAg was specifically expressed in the
LAK cells of these mice, but not in resting T or NK cells, in CTL, or
in any other tissues. Most mice eventually developed a fatal illness
characterized by massive hepatosplenomegaly and disseminated organ
infiltration by large malignant lymphocytes. Cell lines derived from
splenic tumors were TAg+ and NK1.1+ large
granular lymphocytes and displayed variable expression of CD3, CD8, and
CD16. Although these cell lines contained perforin and expressed
granzymes A, B, C, D, and F, they did not exhibit direct cytotoxicity.
Collectively, these results suggest that the 5' flanking
sequences of the human granzyme H gene target expression to an NK/T
progenitor compartment and to activated NK (LAK) cells. Mice and humans
may therefore share a regulatory "program" for the transcription
of NK/LAK specific granzyme genes.
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