Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR)
Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR)
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DOI：
10.15252/embj.2020104730
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发表时间：
2020-07-09
期刊：
影响因子：
11.4
通讯作者：
Su, Xiaolei
中科院分区：
文献类型：
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作者：
Dong, Rui;Libby, Kendra A.;Su, Xiaolei
嵌合抗原受体 (CAR) 指导 T 细胞瞄准并杀死特定的癌细胞。尽管CART疗法在临床上取得了成功，但导致CART细胞激活的细胞内信号通路仍不清楚。使用 CD19CAR 作为模型，我们报告称，与内源性 T 细胞受体 (TCR) 类似，抗原结合会触发 CAR 微簇的形成，从而转导下游信号传导。然而，CAR微簇不会合并成稳定的中心超分子激活簇（cSMAC）。此外，LAT 作为 TCR 信号传导的重要支架蛋白，对于微簇形成、免疫突触形成或 CAR 激活后的肌动蛋白重塑都不是必需的。然而，CART 细胞仍然需要 LAT 才能最佳地产生细胞因子 IL-2。总之，这些数据表明，CART 细胞可以绕过 LAT 以获得下游信号输出的子集，从而揭示了与天然 T 细胞相比的重新布线的信号通路。
The chimeric antigen receptor (CAR) directs T cells to target and kill specific cancer cells. Despite the success ofCART therapy in clinics, the intracellular signaling pathways that lead toCART cell activation remain unclear. UsingCD19CARas a model, we report that, similar to the endogenous T cell receptor (TCR), antigen engagement triggers the formation ofCARmicroclusters that transduce downstream signaling. However,CARmicroclusters do not coalesce into a stable central supramolecular activation cluster (cSMAC). Moreover,LAT, an essential scaffold protein forTCRsignaling, is not required for microcluster formation, immunological synapse formation, nor actin remodeling followingCARactivation. However,CART cells still requireLATfor an optimal production of the cytokineIL-2. Together, these data show thatCART cells can bypassLATfor a subset of downstream signaling outputs, thus revealing a rewired signaling pathway as compared to native T cells.