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

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