Knockdown of human bid gene expression enhances survival of CD8+ T cells.
Tumor cells have developed immune evasion mechanisms such as considerably heterogenous FasL expression on their surface via which they could induce apoptosis of tumor-specific cytotoxic T lymphocytes (CTLs) in the immune system. Meanwhile, the competition of normal immune cells with tumor cells results in relative growth factors shortage for growth and proliferation of nontumor cells, which improves a susceptibility to early apoptosis of CTL. In an attempt to develop strategies for prolonging the survival of adoptively transferred T cells in a hostile pro-apoptotic tumor microenvironment, we used synthetic siRNA and vector-based shRNA to suppress the expression of Bid in human uterocervical carcinoma HeLa cells, followed by the further achievement of Bid gene silencing in human primary cells-CD8(+) lymphocytes via retrovirus-delivered siRNAs. Our results indicated that Bid knockdown HeLa cells are partially resistant to Fas antibody- or serum deprivation-induced apoptosis. Additionally, the blockade of Bid expression in CD8(+) lymphocytes resulted in a less susceptiveness to Fas antibody-induced apoptosis and a survival advantage following recombinant human interleukin-2 (rhIL-2) withdrawal or under lower rhIL-2 concentrations compared with control lymphocytes. These data suggest that knockdown of Bid might serve as an approach to enhancing the survival and tumoricidal activity of T lymphocytes in adoptive immunotherapy.
Lei
Xiao-Ying
XY
Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China.
Xu
Yan-Ming
YM
Wang
Tao
T
Xie
Qiao-Sheng
QS
Jia
Lin-Tao
LT
Wang
Li-Feng
LF
Jin
Bo-Quan
BQ
Yan
Zhen
Z
Yao
Li-Bo
LB
Yang
An-Gang
AG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D051023:BH3 Interacting Domain Death Agonist Protein; C491901:FAS protein, human; D034741:RNA, Small Interfering; D019014:fas Receptor