Wiendl Heinz, Mitsdoerffer Meike, Hofmeister Valeska, Wischhusen Jörg, Bornemann Antje, Meyermann Richard, Weiss Elisabeth H, Melms Arthur, Weller Michael
Department of Neurology, Medical School, University of Tübingen, Tübingen, Germany.
J Immunol. 2002 May 1;168(9):4772-80. doi: 10.4049/jimmunol.168.9.4772.
HLA-G is a nonclassical MHC molecule with highly limited tissue distribution that has been attributed chiefly immune regulatory functions. Glioblastoma is paradigmatic for the capability of human cancers to paralyze the immune system. To delineate the potential role of HLA-G in glioblastoma immunobiology, expression patterns and functional relevance of this MHC class Ib molecule were investigated in glioma cells and brain tissues. HLA-G mRNA expression was detected in six of 12 glioma cell lines in the absence of IFN-gamma and in 10 of 12 cell lines in the presence of IFN-gamma. HLA-G protein was detected in four of 12 cell lines in the absence of IFN-gamma and in eight of 12 cell lines in the presence of IFN-gamma. Immunohistochemical analysis of human brain tumors revealed expression of HLA-G in four of five tissue samples. Functional studies on the role of HLA-G in glioma cells were conducted with alloreactive PBMCs, NK cells, and T cell subpopulations. Expression of membrane-bound HLA-G1 and soluble HLA-G5 inhibited alloreactive and Ag-specific immune responses. Gene transfer of HLA-G1 or HLA-G5 into HLA-G-negative glioma cells (U87MG) rendered cells highly resistant to direct alloreactive lysis, inhibited the alloproliferative response, and prevented efficient priming of cytotoxic T cells. The inhibitory effects of HLA-G were directed against CD8 and CD4 T cells, but appeared to be NK cell independent. Interestingly, few HLA-G-positive cells within a population of HLA-G-negative tumor cells exerted significant immune inhibitory effects. We conclude that the aberrant expression of HLA-G may contribute to immune escape in human glioblastoma.
HLA - G是一种组织分布极为有限的非经典MHC分子，主要具有免疫调节功能。胶质母细胞瘤是人类癌症使免疫系统瘫痪能力的典型代表。为了阐明HLA - G在胶质母细胞瘤免疫生物学中的潜在作用，研究了这种Ib类MHC分子在胶质瘤细胞和脑组织中的表达模式及功能相关性。在12个胶质瘤细胞系中，6个在无干扰素 - γ的情况下检测到HLA - G mRNA表达，10个在有干扰素 - γ的情况下检测到该表达。在12个细胞系中，4个在无干扰素 - γ的情况下检测到HLA - G蛋白，8个在有干扰素 - γ的情况下检测到该蛋白。对人脑肿瘤的免疫组织化学分析显示，5个组织样本中有4个表达HLA - G。利用同种异体反应性PBMC、NK细胞和T细胞亚群对HLA - G在胶质瘤细胞中的作用进行了功能研究。膜结合型HLA - G1和可溶性HLA - G5的表达抑制了同种异体反应性和抗原特异性免疫反应。将HLA - G1或HLA - G5基因转移到HLA - G阴性的胶质瘤细胞（U87MG）中，使细胞对直接的同种异体反应性裂解具有高度抗性，抑制了同种异体增殖反应，并阻止了细胞毒性T细胞的有效启动。HLA - G的抑制作用针对CD8和CD4 T细胞，但似乎与NK细胞无关。有趣的是，在HLA - G阴性肿瘤细胞群体中，少数HLA - G阳性细胞发挥了显著的免疫抑制作用。我们得出结论，HLA - G的异常表达可能有助于人类胶质母细胞瘤的免疫逃逸。
