Lukashev Dmitriy, Klebanov Boris, Kojima Hidefumi, Grinberg Alex, Ohta Akiko, Berenfeld Ludmilla, Wenger Roland H, Ohta Akio, Sitkovsky Michail
New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115, USA.
J Immunol. 2006 Oct 15;177(8):4962-5. doi: 10.4049/jimmunol.177.8.4962.
To evaluate the role of hypoxia-inducible factor 1alpha (HIF-1alpha) 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-1alpha; 2) T cell-targeted HIF-1alpha knockdown; and 3) chimeric mice with HIF-1alpha gene deletion in T and B lymphocytes. In all three types of mice, the HIF-1alpha-deficient T lymphocytes, which were TCR-activated in vitro, produced more proinflammatory cytokines compared with HIF-1alpha-expressing control T cells. Surprisingly, deletion of the I.1 isoform, which represents < 30% of total HIF-1alpha mRNA in activated T cells, was sufficient to markedly enhance TCR-triggered cytokine secretion. These data suggest that HIF-1alpha not only plays a critical role in oxygen homeostasis but also may serve as a negative regulator of T cells.
为了评估缺氧诱导因子1α（HIF-1α）及其TCR激活诱导的短异构体I.1在T细胞功能中的作用，我们通过基因工程构建了独特的小鼠模型：1）敲除HIF-1α的I.1异构体；2）T细胞靶向的HIF-1α敲低；3）T和B淋巴细胞中HIF-1α基因缺失的嵌合小鼠。在所有这三种类型的小鼠中，与表达HIF-1α的对照T细胞相比，体外经TCR激活的HIF-1α缺陷型T淋巴细胞产生了更多的促炎细胞因子。令人惊讶的是，I.1异构体的缺失（在活化T细胞中占总HIF-1α mRNA的不到30%）足以显著增强TCR触发的细胞因子分泌。这些数据表明，HIF-1α不仅在氧稳态中起关键作用，而且可能作为T细胞的负调节因子。
