Clinical and Experimental Immunotherapy Group, Department of Medical Oncology, School of Cancer and Enabling Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Gene Ther. 2012 Nov;19(11):1114-20. doi: 10.1038/gt.2011.192. Epub 2011 Dec 1.
T cells bearing chimeric antigen receptors (CARs) are broadly categorised into first- and second-generation receptors. Second-generation CARs contain a co-stimulatory signalling molecule and have been shown to secrete IL-2, undergo greater proliferation and to have enhanced persistence in vivo. However, we have shown that T cells bearing a first-generation CAR containing a CD19-targeting scFv (single-chain variable fragment) and the CD3ζ-signalling domain are able to produce IL-2 upon co-culture with CD19(+) B-cell lymphomas independent of CD28 activity. Here, we report that signalling through endogenous CD2 following ligation with its ligands, CD48 in mouse and CD58 in humans, drives IL-2 production by first-generation CD19-specific CAR. Moreover, the high levels of IL-2 produced by human T cells engrafted with a second-generation CD28-containing CAR during target-cell recognition are dependent to a degree upon CD2 receptor activity. These observations highlight the fact that the functional activity induced by T-cell-expressed CARs is dependent upon endogenous 'natural' receptor interactions. A deeper understanding of the role of these activities will serve to further refine the design of future CARs to either exploit or avoid these interactions.
嵌合抗原受体 (CAR) 修饰的 T 细胞可广泛分为第一代和第二代受体。第二代 CAR 包含共刺激信号分子，已被证明能分泌 IL-2，在体内具有更大的增殖能力和增强的持久性。然而，我们已经表明，携带靶向 CD19 的 scFv（单链可变片段）和 CD3ζ 信号结构域的第一代 CAR 的 T 细胞能够在与 CD19(+)B 细胞淋巴瘤共培养时产生 IL-2，而不依赖 CD28 活性。在这里，我们报告说，通过与其配体（小鼠中的 CD48 和人类中的 CD58）结合，内源性 CD2 的信号转导驱动第一代 CD19 特异性 CAR 产生 IL-2。此外，在靶细胞识别过程中，带有第二代包含 CD28 的 CAR 移植的人 T 细胞产生的高水平 IL-2 在某种程度上取决于 CD2 受体的活性。这些观察结果强调了一个事实，即 T 细胞表达的 CAR 诱导的功能活性取决于内源性“天然”受体相互作用。更深入地了解这些活动的作用将有助于进一步改进未来 CAR 的设计，以利用或避免这些相互作用。
