Journal
PLOS ONE
Volume 2, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0000853
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Funding
- New England Inflammation and Tissue Protection Institute at Northeastern University, Boston [1R21 AT002788-01]
- National Institutes of Health
- Shriner's Hospital for Children [8560]
- German National Research Foundation [TH733/2-1]
- National Institute of Allergy and Infectious Diseases Intramural program
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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.
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