The Journal of Immunology, 2007, 178: 50.11.
Copyright © 2007 by The American Association of Immunologists, Inc.
LTbR Mediates Cell Contact-Dependent CTL-Directed Anti-Tumor Cytotoxicity
Kebin Liu1,
Najam ud Din1,
Darren D Browing1,
Scott I Abrams2 and
Dafeng Yang1
1 Biochemistry and Molecular Biology, Medical College of Georgia, 1459 Laney walker Blvd, Augusta, GA, 30912,
2 Tumor Immunology and Biology, NCI/NIH, 10 Center Drive, Bethesda, MD, 20892
Abstract
Cytotoxic T lymphocytes (CTLs) are thought to use two cell contact-dependent effector mechanisms, perforin- and Fas-mediated cytotoxicity, to suppress tumor growth. Using a CTL adoptive immunotherapy model, we report here that perforin-deficient CTLs (pfp CTLs) exhibited a significant cytotoxicity against Fas-resistant tumors in vivo. We further demonstrated that the anti-tumor activity is directly mediated by the adoptively transferred CTLs. but does not involve CTL-secreted soluble molecules, such as IFN
and TNF
as lytic agents, since these cytokines exhibited no direct cytotoxicity against these targets. Moreover, it was observed that LT
R, a cell-surface death receptor, is expressed on the tumor cell surface, and LT, LT, and LIGHT, all of which are ligands for LTR, were either constitutively expressed by or activated in the tumor-specific CTLs and primary CD8+ T cells. Silencing LTR in these Fas-resistant tumor cells with LTR-specific shRNA significantly decreased the ability of pfp CTL to mediate tumor rejection in vivo. Taken together, our data suggest that tumor-specific CTL use LTR-mediated cytotoxicity as a third cell contact-dependent effector mechanism against tumor growth in vivo.
