TY - JOUR
T1 - In vivo analysis of adenovirus-specific cytotoxic T lymphocyte response in mice deficient in CD28, Fas ligand, and perforin
AU - Chen, Jian
AU - Hsu, Hui Chen
AU - Zajac, Allan J.
AU - Wu, Qi
AU - Yang, Pingar
AU - Xu, Xin
AU - McPherson, Sylvia A.
AU - Li, Jun
AU - Curiel, David T.
AU - Mountz, John D.
PY - 2006/6
Y1 - 2006/6
N2 - 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-α 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-α, 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.
AB - 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-α 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-α, 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.
UR - http://www.scopus.com/inward/record.url?scp=33745669424&partnerID=8YFLogxK
U2 - 10.1089/hum.2006.17.669
DO - 10.1089/hum.2006.17.669
M3 - Article
C2 - 16776575
AN - SCOPUS:33745669424
SN - 1043-0342
VL - 17
SP - 669
EP - 682
JO - Human Gene Therapy
JF - Human Gene Therapy
IS - 6
ER -