Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival.

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-1alpha) in inflamed and hypoxic areas. Using the
Cre-lox-P-system we generated mice with a T-cell targeted deletion
of the HIF-1alpha gene and analysed them in an in vivo model of
bacterial sepsis. We show that deletion of the HIF-1alpha 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-kappaB activation in TCR activated HIF-1 alpha
deficient T cells. T cells can be recruited to powerfully
contribute to anti-bacterial response if they are relieved from
inhibition by HIF-1alpha 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.