CD69 is a direct HIF-1α target gene in hypoxia as a mechanism enhancing expression on tumor-infiltrating T lymphocytes
CD69 is a direct HIF-1α target gene in hypoxia as a mechanism enhancing expression on tumor-infiltrating T lymphocytes
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DOI：
10.1080/2162402x.2017.1283468
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Melero, Ignacio
中科院分区：
文献类型：
--
作者：
Labiano, Sara;Melendez-Rodriguez, Florinda;Melero, Ignacio
CD 69是T淋巴细胞表面的早期活化标志物，其经历由同源抗原活化。我们观察到强烈表达的CD 69肿瘤浸润T淋巴细胞，居住在缺氧肿瘤微环境，并假设CD 69可以，至少部分，在转录缺氧反应的控制下。与此相一致，在缺氧（1%O-2）条件下培养的人和小鼠CD 3刺激的淋巴细胞显示CD 69在蛋白和mRNA水平上的表达增加。与这些发现相一致的是，最近在体内经历过缺氧的小鼠T淋巴细胞，如哌莫硝唑染色所示，在肿瘤和骨髓缺氧组织区室中更频繁地为CD 69（+）。当使用来自诱导型HIF-1（-/-）小鼠的T淋巴细胞时，以及当观察T细胞为HIF-1（-/-）的小鼠中的肿瘤浸润性T淋巴细胞时，我们都发现了HIF-1参与的证据。通过ChIP实验证明了HIF-1对在人CD 69基因座中发现的新鉴定的缺氧反应元件（HRE）的直接促转录活性。这些结果揭示了HIF-1氧传感通路和CD 69免疫生物学之间的联系。
CD69 is an early activation marker on the surface of T lymphocytes undergoing activation by cognate antigen. We observed intense expression of CD69 on tumor-infiltrating T-lymphocytes that reside in the hypoxic tumor microenvironment and hypothesized that CD69 could be, at least partially, under the control of the transcriptional hypoxia response. In line with this, human and mouse CD3-stimulated lymphocytes cultured under hypoxia (1% O-2) showed increased expression of CD69 at the protein and mRNA level. Consistent with these findings, mouse T lymphocytes that had recently undergone hypoxia in vivo, as denoted by pimonidazole staining, were more frequently CD69(+) in the tumor and bone marrow hypoxic tissue compartments. We found evidence for HIF-1 involvement both when using T-lymphocytes from inducible HIF-1(-/-) mice and when observing tumor-infiltrating T-lymphocytes in mice whose T cells are HIF-1(-/-). Direct pro-transcriptional activity of HIF-1 on a newly identified hypoxia response element (HRE) found in the human CD69 locus was demonstrated by ChIP experiments. These results uncover a connection between the HIF-1 oxygen-sensing pathway and CD69 immunobiology.