[HTML][HTML] Targeted deletion of HIF-1α gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival
M Thiel, CC Caldwell, S Kreth, S Kuboki, P Chen… - PLoS …, 2007 - journals.plos.org
M Thiel, CC Caldwell, S Kreth, S Kuboki, P Chen, P Smith, A Ohta, AB Lentsch, D Lukashev…
PLoS One, 2007•journals.plos.orgBackground Sepsis patients may die either from an overwhelming systemic immune
response and/or from an immunoparalysis-associated lack of anti-bacterial immune
defence. We hypothesized that bacterial superantigen-activated T cells may be prevented
from contribution into anti-bacterial response due to the inhibition of their effector functions
by the hypoxia inducible transcription factor (HIF-1α) in inflamed and hypoxic areas.
Methodology/Principal Findings Using the Cre-lox-P-system we generated mice with a T …
response and/or from an immunoparalysis-associated lack of anti-bacterial immune
defence. We hypothesized that bacterial superantigen-activated T cells may be prevented
from contribution into anti-bacterial response due to the inhibition of their effector functions
by the hypoxia inducible transcription factor (HIF-1α) in inflamed and hypoxic areas.
Methodology/Principal Findings Using the Cre-lox-P-system we generated mice with a T …
Background
Sepsis patients may die either from an overwhelming systemic immune response and/or from an immunoparalysis-associated lack of anti-bacterial immune defence. We hypothesized that bacterial superantigen-activated T cells may be prevented from contribution into anti-bacterial response due to the inhibition of their effector functions by the hypoxia inducible transcription factor (HIF-1α) in inflamed and hypoxic areas.
Methodology/Principal Findings
Using the Cre-lox-P-system we generated mice with a T–cell targeted deletion of the HIF-1α gene and analysed them in an in vivo model of bacterial sepsis. We show that deletion of the HIF-1α gene leads to higher levels of pro-inflammatory cytokines, stronger anti-bacterial effects and much better survival of mice. These effects can be at least partially explained by significantly increased NF-κB activation in TCR activated HIF-1 α deficient T cells.
Conclusions/Significance
T cells can be recruited to powerfully contribute to anti-bacterial response if they are relieved from inhibition by HIF-1α in inflamed and hypoxic areas. Our experiments uncovered the before unappreciated reserve of anti-bacterial capacity of T cells and suggest novel therapeutic anti-pathogen strategies based on targeted deletion or inhibition of HIF-1 α in T cells.
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