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J. Biol. Chem., Vol. 279, Issue 25, 26581-26587, June 18, 2004

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Discordant Regulation of Granzyme H and Granzyme B Expression in Human Lymphocytes^*

Karin A. Sedelies, Thomas J. Sayers¶, Kirsten M. Edwards||, Weisan Chen**, Daniel G. Pellicci, Dale I. Godfrey, and Joseph A. Trapani¶¶

From the Cancer Immunology Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, East Melbourne, 8006, Australia, the ^¶Basic Research program, SAIC-Frederick Inc., NCI, National Institutes of Health, Frederick, MD, 21702, the ^**Ludwig Institute for Cancer Research, Austin and Repatriation Medical Center, Studley Road, Heidelberg, 3084, Australia, and the Department of Pathology and Immunology, Monash University Medical School, Melbourne, Victoria 3181, Australia

We analyzed the expression of granzyme H in human blood leukocytes, using a novel monoclonal antibody raised against recombinant granzyme H. 33-kDa granzyme H was easily detected in unfractionated peripheral blood mononuclear cells, due to its high constitutive expression in CD3^-CD56⁺ natural killer (NK) cells, whereas granzyme B was less abundant. The NK lymphoma cell lines, YT and Lopez, also expressed high granzyme H levels. Unstimulated CD4⁺ and particularly CD8⁺ T cells expressed far lower levels of granzyme H than NK cells, and various agents that classically induce T cell activation, proliferation, and enhanced granzyme B expression failed to induce granzyme H expression in T cells. Also, granzyme H was not detected in NK T cells, monocytes, or neutrophils. There was a good correlation between mRNA and protein expression in cells that synthesize both granzymes B and H, suggesting that gzmH gene transcription is regulated similarly to gzmB. Overall, our data indicate that although the gzmB and gzmH genes are tightly linked, expression of the proteins is quite discordant in T and NK cells. The finding that granzyme H is frequently more abundant than granzyme B in NK cells is consistent with a role for granzyme H in complementing the pro-apoptotic function of granzyme B in human NK cells.

Received for publication, November 14, 2003 , and in revised form, April 5, 2004.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U. S. government.

^* This work was supported in part by federal funds from the NCI, National Institutes of Health, under Contract N01-CO-56000. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by project grants and a research fellowship from the National Health and Medical Research Council of Australia.

^|| Present address: Dept. of Pathology and Harvard Center for Cancer Biology, Harvard Medical School, Boston, MA 02115.

Present address: Dept. of Microbiology and Immunology, University of Melbourne, Parkville, 3052, Australia.

^¶¶ Supported by a research fellowship from the National Health and Medical Research Council of Australia. To whom correspondence should be addressed. Tel.: 61-3-9656-3726; Fax: 61-3-9656-1411; E-mail: joe.trapani{at}petermac.org.

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