Labiano Sara, Meléndez-Rodríguez Florinda, Palazón Asís, Teijeira Álvaro, Garasa Saray, Etxeberria Iñaki, Aznar M Ángela, Sánchez-Paulete Alfonso R, Azpilikueta Arantza, Bolaños Elixabet, Molina Carmen, de la Fuente Hortensia, Maiso Patricia, Sánchez-Madrid Francisco, de Landázuri Manuel Ortiz, Aragonés Julián, Melero Ignacio
Immunology and Immunotherapy Department, Center for Applied Medical Research (CIMA) and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
Research Unit, Santa Cristina Hospital, Research Institute Princesa (IP), Autonomous University of Madrid, Madrid, Spain.
Oncoimmunology. 2017 Jan 19;6(4):e1283468. doi: 10.1080/2162402X.2017.1283468. eCollection 2017.
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) showed increased expression of CD69 at the protein and mRNA level. Consistent with these findings, mouse T lymphocytes that had recently undergone hypoxia , as denoted by pimonidazole staining, were more frequently CD69 in the tumor and bone marrow hypoxic tissue compartments. We found evidence for HIF-1α involvement both when using T-lymphocytes from inducible HIF-1α mice and when observing tumor-infiltrating T-lymphocytes in mice whose T cells are HIF-1α. Direct pro-transcriptional activity of HIF-1α 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-1α oxygen-sensing pathway and CD69 immunobiology.
CD69是经同源抗原激活的T淋巴细胞表面的早期激活标志物。我们观察到，存在于缺氧肿瘤微环境中的肿瘤浸润性T淋巴细胞上CD69表达强烈，并推测CD69可能至少部分受转录性缺氧反应的调控。与此相符的是，在缺氧（1%氧气）条件下培养的人及小鼠CD3刺激的淋巴细胞在蛋白质和mRNA水平上CD69表达增加。与这些发现一致的是，如用匹莫硝唑染色所示，最近经历过缺氧的小鼠T淋巴细胞在肿瘤和骨髓缺氧组织区室中更频繁地表达CD69。无论是使用来自诱导型HIF-1α小鼠的T淋巴细胞，还是观察T细胞为HIF-1α的小鼠中的肿瘤浸润性T淋巴细胞，我们都发现了HIF-1α参与的证据。染色质免疫沉淀实验证明了HIF-1α对人CD69基因座中一个新发现的缺氧反应元件（HRE）具有直接的转录前活性。这些结果揭示了HIF-1α氧感应途径与CD69免疫生物学之间的联系。
