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CUTTING EDGE |
and Its Activation-Inducible Short Isoform I.1 Negatively Regulate Functions of CD4+ and CD8+ T Lymphocytes
* New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA;
Division of Immunology, Institute for Medical Science, Dokkyo University School of Medicine, Tochigi, Japan;
Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; and
Institute of Physiology and Center for Integrative Human Physiology (CIHP), University of Zurich, Zurich, Switzerland
To evaluate the role of hypoxia-inducible factor 1
(HIF-1) 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-1; 2) T cell-targeted HIF-1 knockdown; and 3) chimeric mice with HIF-1 gene deletion in T and B lymphocytes. In all three types of mice, the HIF-1-deficient T lymphocytes, which were TCR-activated in vitro, produced more proinflammatory cytokines compared with HIF-1-expressing control T cells. Surprisingly, deletion of the I.1 isoform, which represents <30% of total HIF-1 mRNA in activated T cells, was sufficient to markedly enhance TCR-triggered cytokine secretion. These data suggest that HIF-1 not only plays a critical role in oxygen homeostasis but also may serve as a negative regulator of T cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to: Dr. Michail Sitkovsky, New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, 113MU, Boston, MA 02115. E-mail address: m.sitkovsky{at}neu.edu
2 Abbreviations used in this paper: HIF-1, hypoxia-inducible factor 1; ES cells, embryonic stem cell.
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