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

PLoS One. 2007 Sep 5;2(9):e853. doi: 10.1371/journal.pone.0000853.


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-1alpha) 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-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.

Conclusions/significance: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Flow Cytometry
  • Hypoxia / pathology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Lymphocyte Activation
  • Mice
  • NF-kappa B / metabolism
  • Peritonitis / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sepsis / genetics
  • Sepsis / pathology*
  • Survival Rate
  • T-Lymphocytes / metabolism*


  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NF-kappa B