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Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305
Granulysin (GNLY) is a cytolytic molecule expressed by human CTL and NK cells with activity against a variety of tumors and microbes, including Mycobacterium tuberculosis. Although the molecular mechanism of GNLY-induced apoptosis of Jurkat T cells is well defined in vitro, no direct evidence for its in vivo effects has been demonstrated. Because there is no murine homologue of GNLY, we generated mice expressing GNLY using a bacterial artificial chromosome containing the human GNLY gene and its 5' and 3' flanking regions. GNLY is expressed in leukocytes from transgenic mice with similar kinetics as in PBMC from humans: GNLY is constitutively expressed in NK cells and, following stimulation through the TCR, appears in T lymphocytes 8–10 days after activation. Both forms of GNLY (9 and 15 kDa) are produced by activated T cells, whereas the 15-kDa form predominates in freshly isolated NK cells from transgenic animals. GNLY mRNA is highest in spleen, with detectable expression in thymus and lungs, and minimal expression in heart, kidney, liver, muscle, intestine, and brain. Allospecific cell lines generated from GNLY transgenic animals showed enhanced killing of target cells. In vivo effects of GNLY were evaluated using the syngeneic T lymphoma tumor C6VL. GNLY transgenic mice survived significantly longer than nontransgenic littermates in response to a lethal tumor challenge. These findings demonstrate for the first time an in vivo effect of GNLY and suggest that GNLY may prove a useful therapeutic modality for the treatment of cancer.
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.
1 This research was supported by National Institutes of Health Grant AI43348 (to A.M.K.). A.M.K. is the Shelagh Galligan Professor of Pediatrics.
2 Address correspondence and reprint requests to Dr. Alan M. Krensky, Department of Pediatrics, Stanford University School of Medicine, Center for Clinical Science Research 2105, 300 Pasteur Drive, Stanford, CA 94305-5164. E-mail address: Krensky{at}stanford.edu
3 Abbreviations used in this paper: GNLY, granulysin; BAC, bacterial artificial chromosome; Ct, cycle threshold; FloKA, flow-based killing assay; GUS, 
-glucoronidase; qRT-PCR, quantitative real-time RT-PCR; SnRNP, small nuclear ribonucleoprotein; SFTPB, surfactant pulmonary-associated protein B.
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  H. Zhang, C. Zhong, L. Shi, Y. Guo, and Z. Fan Granulysin Induces Cathepsin B Release from Lysosomes of Target Tumor Cells to Attack Mitochondria through Processing of Bid Leading to Necroptosis J. Immunol., June 1, 2009; 182(11): 6993 - 7000. [Abstract] [Full Text] [PDF]
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