Natural killer T cells exacerbate liver injury in a transforming growth factor β receptor II dominant-negative mouse model of primary biliary cirrhosis

Hepatology ◽  
2007 ◽  
Vol 47 (2) ◽  
pp. 571-580 ◽  
Author(s):  
Ya-Hui Chuang ◽  
Zhe-Xiong Lian ◽  
Guo-Xiang Yang ◽  
Shang-An Shu ◽  
Yuki Moritoki ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Primary Biliary Cirrhosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Natural Killer T Cells ◽  
Dominant Negative ◽  
Biliary Cirrhosis ◽  
Β Receptor ◽  
Killer T Cells

Adapting a transforming growth factor β–related tumor protection strategy to enhance antitumor immunity

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3179-3187 ◽  
Author(s):  
Catherine M. Bollard ◽  
Claudia Rössig ◽  
M. Julia Calonge ◽  
M. Helen Huls ◽  
Hans-Joachim Wagner ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Signal Transduction Pathway ◽  
Green Fluorescence Protein ◽  
Transforming Growth Factor Β ◽  
Dominant Negative ◽  
Barr Virus ◽  
Specific Ctls ◽  
Epstein Barr ◽  
Β Receptor

Abstract Transforming growth factor β (TGF-β), a pleiotropic cytokine that regulates cell growth and differentiation, is secreted by many human tumors and markedly inhibits tumor-specific cellular immunity. Tumors can avoid the differentiating and apoptotic effects of TGF-β by expressing a nonfunctional TGF-β receptor. We have determined whether this immune evasion strategy can be manipulated to shield tumor-specific cytotoxic T lymphocytes (CTLs) from the inhibitory effects of tumor-derived TGF-β. As our model we used Epstein-Barr virus (EBV)–specific CTLs that are infused as treatment for EBV-positive Hodgkin disease but that are vulnerable to the TGF-β produced by this tumor. CTLs were transduced with a retrovirus vector expressing the dominant-negative TGF-β type II receptor HATGF-βRII-Δcyt. HATGF-βRII-Δcyt– but not green fluorescence protein (eGFP)–transduced CTLs was resistant to the antiproliferative and anticytotoxic effects of exogenous TGF-β. Additionally, receptor-transduced cells continued to secrete cytokines in response to antigenic stimulation. TGF-β receptor ligation results in phosphorylation of Smad2, and this pathway was disrupted in HATGF-βRII-Δcyt–transduced CTLs, confirming blockade of the signal transduction pathway. Long-term expression of TGF-βRII-Δcyt did not affect CTL function, phenotype, or growth characteristics. Tumor-specific CTLs expressing HATGF-βRII-Δcyt should have a selective functional and survival advantage over unmodified CTLs in the presence of TGF-β–secreting tumors and may be of value in treatment of these diseases.

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