Lopez R D, Xu S, Guo B, Negrin R S, Waller E K
Division of Bone Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, USA.
Blood. 2000 Dec 1;96(12):3827-37.
The ability of human gamma delta-T cells to mediate a number of in vitro functions, including innate antitumor and antiviral activity, suggests these cells can be exploited in selected examples of adoptive immunotherapy. To date, however, studies to examine such issues on a clinical scale have not been possible, owing in large measure to the difficulty of obtaining sufficient numbers of viable human gamma delta-T cells given their relative infrequency in readily available tissues. Standard methods used to expand human T cells often use a combination of mitogens, such as anti-T-cell receptor antibody OKT3 and interleukin (IL)-2. These stimuli, though promoting the expansion of alpha beta-T cells, usually do not promote the efficient expansion of gamma delta-T cells. CD2-mediated, IL-12-dependent signals that result in the selective expansion of human gamma delta-T cells from cultures of mitogen-stimulated human peripheral blood mononuclear cells are identified. It is first established that human gamma delta-T cells are exquisitely sensitive to apoptosis induced by T-cell mitogens OKT3 and IL-2. Next it is shown that the CD2-mediated IL-12-dependent signals, which lead to the expansion of gamma delta-T cells, do so by selectively protecting subsets of human gamma delta-T cells from mitogen-induced apoptosis. Finally, it is demonstrated that apoptosis-resistant gamma delta-T cells are capable of mediating significant antitumor cytotoxicity against a panel of human-derived tumor cell lines in vitro. Both the biologic and the practical implications of induced resistance to apoptosis in gamma delta-T cells are considered and discussed because these findings may play a role in the development of new forms of adoptive cellular immunotherapy. (Blood. 2000;96:3827-3837)
人类γδ-T细胞具有介导多种体外功能的能力，包括先天性抗肿瘤和抗病毒活性，这表明这些细胞可用于某些过继性免疫治疗实例。然而，迄今为止，由于在容易获得的组织中人类γδ-T细胞相对稀少，难以获得足够数量的活细胞，因此无法在临床规模上研究此类问题。用于扩增人类T细胞的标准方法通常使用有丝分裂原的组合，如抗T细胞受体抗体OKT3和白细胞介素（IL）-2。这些刺激虽然能促进αβ-T细胞的扩增，但通常不能促进γδ-T细胞的有效扩增。已鉴定出CD2介导的、IL-12依赖性信号，该信号可导致有丝分裂原刺激的人类外周血单个核细胞培养物中人类γδ-T细胞的选择性扩增。首先确定人类γδ-T细胞对T细胞有丝分裂原OKT3和IL-2诱导的凋亡极为敏感。接下来表明，导致γδ-T细胞扩增的CD2介导的IL-12依赖性信号，是通过选择性保护人类γδ-T细胞亚群免受有丝分裂原诱导的凋亡来实现的。最后证明，抗凋亡的γδ-T细胞能够在体外对一组人类来源的肿瘤细胞系介导显著的抗肿瘤细胞毒性。考虑并讨论了γδ-T细胞中诱导抗凋亡的生物学和实际意义，因为这些发现可能在新型过继性细胞免疫治疗的发展中发挥作用。（《血液》。2000年；96:3827 - 3837）
