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CTLs Contain and Use Intracellular Stores of FasL Distinct from Cytolytic Granules¹

Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada

CTL lyse target cells through the release of cytolytic granule contents and cell surface expression of Fas ligand (FasL). Current models suggest that FasL is stored in cytolytic granules and that FasL cell surface expression would be subject to the same controls as degranulation. We demonstrate that murine CTLs undergo two waves of FasL cell surface expression after stimulation. The first wave is from a pre-existing pool of FasL, and the second wave requires new protein synthesis. Signaling for FasL expression appears to be finely tuned as a weak signal preferentially induced surface translocation of the stored FasL, whereas a strong signal preferentially triggered the expression of de novo synthesized FasL. The early FasL is differentially regulated from degranulation, as there were multiple circumstances whereby rapid FasL cell surface expression and FasL-dependent killing occurred in the absence of detectable degranulation. Furthermore, we found through confocal microscopy that stored FasL resides in vesicles distinct from cytolytic granules. Our data clearly show that CTL degranulation and FasL lytic mechanisms are fully independent with respect to stored component localization and regulation.

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 work was supported by the National Cancer Institute of Canada with funds from the Canadian Cancer Society. H.L.O. and J.-S.H. are supported by Scientist and Studentship awards, respectively, from the Alberta Heritage Foundation for Medical Research.

² Address correspondence and reprint requests to Dr. Hanne L. Ostergaard, Department of Medical Microbiology and Immunology, 670 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada. E-mail address: hanne.ostergaard{at}ualberta.ca

³ Abbreviations used in this paper: FasL, Fas ligand; CHX, cycloheximide; LAMP1, lysosomal-associated membrane protein-1; MMP, matrix metalloprotease; PEL, peritoneal exudate lymphocytes; CS, calf serum.

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