Targeted deletion of HIF-1alpha 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-1alpha) in inflamed and hypoxic areas.


RESULTS
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
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.
Thiel
Manfred
M
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Caldwell
Charles C
CC
Kreth
Simone
S
Kuboki
Satoshi
S
Chen
P
P
Smith
Patrick
P
Ohta
Akio
A
Lentsch
Alex B
AB
Lukashev
Dmitry
D
Sitkovsky
Michail V
MV
D000818:Animals; D005434:Flow Cytometry; D000860:Hypoxia / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010538:Peritonitis / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000235:genetics / Q000473:pathology*; D015996:Survival Rate; D013601:T-Lymphocytes / Q000378:metabolism*