Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival.
<h4>Background</h4>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-bact...
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Public Library of Science (PLoS)
2007-09-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000853&type=printable |
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| author | Manfred Thiel Charles C Caldwell Simone Kreth Satoshi Kuboki P Chen Patrick Smith Akio Ohta Alex B Lentsch Dmitry Lukashev Michail V Sitkovsky |
| author_facet | Manfred Thiel Charles C Caldwell Simone Kreth Satoshi Kuboki P Chen Patrick Smith Akio Ohta Alex B Lentsch Dmitry Lukashev Michail V Sitkovsky |
| author_sort | Manfred Thiel |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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. |
| format | Article |
| id | doaj-art-e6e358e7d42a45b082ebdf1c1d7744db |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2007-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-e6e358e7d42a45b082ebdf1c1d7744db2025-08-20T02:38:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032007-09-0129e85310.1371/journal.pone.0000853Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival.Manfred ThielCharles C CaldwellSimone KrethSatoshi KubokiP ChenPatrick SmithAkio OhtaAlex B LentschDmitry LukashevMichail V Sitkovsky<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000853&type=printable |
| spellingShingle | Manfred Thiel Charles C Caldwell Simone Kreth Satoshi Kuboki P Chen Patrick Smith Akio Ohta Alex B Lentsch Dmitry Lukashev Michail V Sitkovsky Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. PLoS ONE |
| title | Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. |
| title_full | Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. |
| title_fullStr | Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. |
| title_full_unstemmed | Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. |
| title_short | Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. |
| title_sort | targeted deletion of hif 1alpha gene in t cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000853&type=printable |
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