Cutting edge: hypoxia-inducible factor 1α and its activation-inducible short isoform I. 1 negatively regulate functions of CD4+ and CD8+ T lymphocytes

D Lukashev, B Klebanov, H Kojima… - The Journal of …, 2006 - journals.aai.org
D Lukashev, B Klebanov, H Kojima, A Grinberg, A Ohta, L Berenfeld, RH Wenger, A Ohta…
The Journal of Immunology, 2006journals.aai.org
To evaluate the role of hypoxia-inducible factor 1α (HIF-1α) and its TCR activation-inducible
short isoform I. 1 in T cell functions, we genetically engineered unique mice with: 1) knockout
of I. 1 isoform of HIF-1α; 2) T cell-targeted HIF-1α knockdown; and 3) chimeric mice with HIF-
1α gene deletion in T and B lymphocytes. In all three types of mice, the HIF-1α-deficient T
lymphocytes, which were TCR-activated in vitro, produced more proinflammatory cytokines
compared with HIF-1α-expressing control T cells. Surprisingly, deletion of the I. 1 isoform …
Abstract
To evaluate the role of hypoxia-inducible factor 1α (HIF-1α) and its TCR activation-inducible short isoform I. 1 in T cell functions, we genetically engineered unique mice with: 1) knockout of I. 1 isoform of HIF-1α; 2) T cell-targeted HIF-1α knockdown; and 3) chimeric mice with HIF-1α gene deletion in T and B lymphocytes. In all three types of mice, the HIF-1α-deficient T lymphocytes, which were TCR-activated in vitro, produced more proinflammatory cytokines compared with HIF-1α-expressing control T cells. Surprisingly, deletion of the I. 1 isoform, which represents< 30% of total HIF-1α mRNA in activated T cells, was sufficient to markedly enhance TCR-triggered cytokine secretion. These data suggest that HIF-1α not only plays a critical role in oxygen homeostasis but also may serve as a negative regulator of T cells.
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