Wischhusen Jörg, Friese Manuel A, Mittelbronn Michel, Meyermann Richard, Weller Michael
Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie Institute for ClinicaI Brain Research, University of Tübingen Medical School, Tübingen, Germany.
J Neuropathol Exp Neurol. 2005 Jun;64(6):523-8. doi: 10.1093/jnen/64.6.523.
The nonclassical MHC class I molecule HLA-E is the only known ligand for CD94/NKG2A and CD94/NKG2C expressed on NK and CD8+ alphabeta and gammadelta T cells. HLA-E may transmit either activating signals via CD94/NKG2C or inhibitory signals mediated by CD94/NKG2A. Here we show that HLA-E is expressed at mRNA and protein level in human long-term glioma cell lines, primary ex vivo polyclonal glioblastoma cell cultures and surgical glioblastoma specimens. Furthermore, immunohistochemistry revealed an enhanced in vivo expression of HLA-E in gliomas of lower grades and a massive overexpression in grade IV glioblastomas compared with normal CNS tissue. An immune-inhibitory effect of HLA-E on tumor-specific CTL has already been described. We show that siRNA-mediated silencing of HLA-E or blocking of CD94/NKG2A enables NKG2D-mediated lysis of 51Cr-labeled tumor cells by NK cells. Thus, our study provides the first evidence that expression and interaction of HLA-E on cancer cells with CD94/NKG2A expressed on lymphocytes compromises innate anti-tumor immune responses.
非经典MHC I类分子HLA-E是自然杀伤细胞（NK）、CD8⁺αβ和γδ T细胞表面表达的CD94/NKG2A和CD94/NKG2C唯一已知的配体。HLA-E可通过CD94/NKG2C传递激活信号，或通过CD94/NKG2A介导抑制信号。在此我们发现，HLA-E在人长期胶质瘤细胞系、原代体外多克隆胶质母细胞瘤细胞培养物及手术切除的胶质母细胞瘤标本中均有mRNA和蛋白水平的表达。此外，免疫组化显示，与正常中枢神经系统组织相比，HLA-E在低级别胶质瘤中体内表达增强，在IV级胶质母细胞瘤中大量过表达。HLA-E对肿瘤特异性细胞毒性T淋巴细胞（CTL）的免疫抑制作用已有报道。我们发现，siRNA介导的HLA-E沉默或CD94/NKG2A阻断可使NK细胞通过NKG2D介导对⁵¹Cr标记的肿瘤细胞进行杀伤。因此，我们的研究首次证明，癌细胞上的HLA-E与淋巴细胞上表达的CD94/NKG2A之间的表达及相互作用会损害先天性抗肿瘤免疫反应。
