CD16+ γδ T cells mediate antibody dependent cellular cytotoxicity:: Potential mechanism in the pathogenesis of multiple sclerosis
CD16+ γδ T cells mediate antibody dependent cellular cytotoxicity:: Potential mechanism in the pathogenesis of multiple sclerosis
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DOI：
10.1016/j.clim.2008.03.513
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发表时间：
2008-08-01
影响因子：
8.6
通讯作者：
Freedman, Mark S.
中科院分区：
文献类型：
--
作者：
Chen, Zhihong;Freedman, Mark S.
我们的总体目标是了解γ δ T细胞在中枢神经系统（CNS）自身免疫性疾病多发性硬化症（MS）发病机制中的作用。我们已经证明γ δ T细胞在体外对CNS细胞具有直接细胞毒性。虽然MS损伤的确切机制尚不清楚，但最近的证据表明B细胞和髓鞘抗体的作用。因此，我们有兴趣研究γ δ T细胞是否可以通过涉及抗体依赖性细胞毒性的间接机制损伤CNS细胞。为了研究这一点，我们开发了一种体外流式细胞术细胞毒性试验（称为“FC（3）A”）来定量细胞毒性的量。我们利用已知的靶细胞（伯基特氏B淋巴瘤），以及抗CD20的单克隆抗体（mAb），利妥昔单抗，靶细胞首先用利妥昔单抗包被，然后与来自MS患者的γ δ T细胞共培养。（其仅在核破裂指示细胞死亡时增加）。我们确定这种溶解是由于表达CD16（Fc γ受体）的γ δ T细胞，因此能够结合利妥昔单抗并通过ADCC介导细胞溶解。这种特异性细胞溶解与利妥昔单抗浓度、E：T比率和γ δ T细胞上的CD16表面表达相关。这些发现为γ δ T细胞在MS免疫发病机制中的作用提供了新的视角，并深入了解利妥昔单抗在MS治疗中的潜在治疗作用之一。此外，我们开发的这种新的FC（3）A方法可以很容易地适用于研究其他类型的疑似ADCC型杀伤的免疫细胞。(c)2008年爱思唯尔公司All rights reserved.
Our overall objective is to understand the role of gamma delta T cells in the pathogenesis of the central nervous system (CNS) autoimmune disease multiple sclerosis (MS). We have demonstrated that gamma delta T cells are directly cytotoxic to CNS cells in vitro. Although the exact mechanism of damage in MS is unknown, recent evidence suggests a role for B cells and antibodies to myelin. We were therefore interested in examining whether gamma delta T cells can injure CNS cells via an indirect mechanism involving antibody dependent cellular cytotoxicity. To study this we developed an in vitro flow cytometric cellular cytotoxicity assay (called "FC(3)A") to quantitate the amount of cytotoxicity. We utilized known target cells (Burkitt's B lymphoma) that express CD20, together with a monoclonal antibody (mAb) to CD20, rituximab, that is being studied as a potential treatment for MS. Target cells are first coated with rituximab followed by co-culture with gamma delta T cells derived from patients with MS. Specific lysis of target cells was determined by quantitation of 7-AAD (which increases only upon nuclear disruption indicating cell death). We determined that this lysis was due to gamma delta T cells that express CD16 (Fc gamma receptor) and were therefore capable of binding the rituximab and mediating cytolysis via ADCC. This specific cell lysis correlated with rituximab concentration, E:T ratio, and the surface expression of CD16 on gamma delta T cells. These findings provide a new perspective with regards to the role of gamma delta T cells in the immunopathogenesis of MS and an insight into one of the potential therapeutic effects of rituximab in the treatment of MS. In addition, this new FC(3)A method we developed could readily be adapted to study other types of immune cells suspected of ADCC-type killing. (c) 2008 Elsevier Inc. All rights reserved.