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Hum Gene Ther. 2006 Jun;17(6):669-82.

In vivo analysis of adenovirus-specific cytotoxic T lymphocyte response in mice deficient in CD28, fas ligand, and perforin.

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1
Department of Medicine, University of Alabama at Birmingham, and Veterans Administration Medical Center, Birmingham, AL 35294, USA.

Abstract

Adenoviruses (Ad) have been extensively studied as gene delivery vectors in gene therapy and as vaccine carriers. The cell-mediated cytotoxicity induced by Ad is of great interest in both applications. However, the mechanism underlying Ad-specific cytotoxic T lymphocyte (CTL) generation and effector function remains unclear. In this study, we used a novel MHC class I tetramer and an in vivo CTL assay to examine the role of CD28, perforin, Fas ligand (FasL), and TNF-alpha in the generation and function of Ad-specific CTLs in vivo. During the primary response, there was a significant defect in both the generation and in vivo effector function of Ad-specific CTLs in CD28-/- mice, but not in CD4+ T cell-depleted mice or CD4-/- mice. The relative role of CTL effector molecules was assayed by in vivo CTL assay in perforin- or FasL-mutant mice, using donor cells from Fas-deficient or TNFR1/TNFR2-deficient mice. The results indicated that the in vivo CTL activity is mediated mainly by perforin. In the absence of perforin, production of FasL, but not TNF-alpha, by the CTLs results in lower level Ad-specific killing of target cells. These results provide important implications concerning the development of safe and effective Ad vectors for gene therapy and vaccines.

PMID:
16776575
DOI:
10.1089/hum.2006.17.669
[Indexed for MEDLINE]
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