Targeted Deletion of HIF-1[alpha] Gene in T Cells Prevents their Inhibition in Hypoxic Inflamed Tissues and Improves Septic Mice Survival

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-1[alpha]) 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-1[alpha] gene and analysed them in an in vivo model of bacterial sepsis. We show that deletion of the HIF-1[alpha] 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-[kappa]B activation in TCR activated HIF-1 [alpha] 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-1[alpha] 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 [alpha] in T cells.