Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR).,The EMBO Journal

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Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR).
The EMBO Journal ( IF 11.4 ) Pub Date : 2020-07-09 , DOI: 10.15252/embj.2020104730
Rui Dong ₁ , Kendra A Libby _{2,

3} , Franziska Blaeschke _{4,

5,

6} , Walker Fuchs _{2,

7} , Alexander Marson _{4,

5,

6,

8,

9,

10,

11,

12} , Ronald D Vale _{1,

13} , Xiaolei Su _{2,

14}

Affiliation

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
Department of Cell Biology, Yale School of Medicine, New Haven, CT, USA.
Yale College, New Haven, CT, USA.
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
Yale Combined Program in the Biological and Biomedical Sciences, New Haven, CT, USA.
Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, CA, USA.
Chan Zuckerberg Biohub, San Francisco, CA, USA.
UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
The Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
Yale Cancer Center, Yale University, New Haven, CT, USA.

The chimeric antigen receptor (CAR) directs T cells to target and kill specific cancer cells. Despite the success of CAR T therapy in clinics, the intracellular signaling pathways that lead to CAR T cell activation remain unclear. Using CD19 CAR as a model, we report that, similar to the endogenous T cell receptor (TCR), antigen engagement triggers the formation of CAR microclusters that transduce downstream signaling. However, CAR microclusters do not coalesce into a stable central supramolecular activation cluster (cSMAC). Moreover, LAT, an essential scaffold protein for TCR signaling, is not required for microcluster formation, immunological synapse formation, nor actin remodeling following CAR activation. However, CAR T cells still require LAT for an optimal production of the cytokine IL‐2. Together, these data show that CAR T cells can bypass LAT for a subset of downstream signaling outputs, thus revealing a rewired signaling pathway as compared to native T cells.

中文翻译：

表达嵌合抗原受体 (CAR) 的 T 细胞中重新布线的信号网络。

嵌合抗原受体 (CAR) 指导 T 细胞靶向并杀死特定的癌细胞。尽管 CAR T 疗法在临床上取得了成功，但导致 CAR T 细胞活化的细胞内信号通路仍不清楚。使用 CD19 CAR 作为模型，我们报告说，类似于内源性 T 细胞受体 (TCR)，抗原参与触发了转导下游信号的 CAR 微簇的形成。然而，CAR 微簇不会合并成稳定的中央超分子激活簇 (cSMAC)。此外，LAT 是 TCR 信号传导的必要支架蛋白，微簇形成、免疫突触形成和 CAR 激活后肌动蛋白重塑都不需要。然而，CAR T 细胞仍然需要 LAT 才能最佳地产生细胞因子 IL-2。一起，

更新日期：2020-08-17

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