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cBAF复合体成分和MYC在CD8+T细胞命运的早期中合作
2022-06-26 17:45
来源：小柯机器人

美国圣犹德儿童研究医院Douglas R. Green、Hongbo Chi等研究人员合作发现，cBAF复合体成分和MYC在CD8+T细胞命运的早期中合作。该项研究成果于2022年6月22日在线发表在《自然》杂志上。

使用基于CRISPR的体内记忆T（Tmem）细胞生成负调控因子的筛选，研究人员确定了哺乳动物典型BRG1/BRM相关因子（cBAF）的多种成分。cBAF复合物的几个成分对活化的CD8+T细胞分化为T效应（Teff）细胞至关重要，它们的丢失会促进体内Tmem细胞的形成。在活化的CD8+T细胞的第一次分裂中，cBAF和MYC经常不对称地共同分配到两个子细胞中。
 
具有高MYC和高cBAF的子细胞显示出朝向Teff细胞的细胞命运轨迹，而具有低MYC和低cBAF的子细胞则优先向Tmem细胞分化。cBAF复合物和MYC的物理相互作用建立了活化CD8+T细胞的染色质结构。在产生嵌合抗原受体T（CAR-T）细胞之前，用一种潜在的cBAF抑制剂在激活的头48小时内处理新生的CD8+T细胞，可明显提高小鼠实体瘤模型的疗效。
 
这些结果确立了cBAF是Tmem细胞命运的负面决定因子，并表明在T细胞分化早期操纵cBAF可以改善癌症免疫疗法。
 
据介绍，识别促进Tmem细胞的机制对疫苗接种和抗癌免疫治疗有重要意义。
 
附：英文原文
 
Title: cBAF complex components and MYC cooperate early in CD8+ T cell fate

Author: Guo, Ao, Huang, Hongling, Zhu, Zhexin, Chen, Mark J., Shi, Hao, Yuan, Sujing, Sharma, Piyush, Connelly, Jon P., Liedmann, Swantje, Dhungana, Yogesh, Li, Zhenrui, Haydar, Dalia, Yang, Mao, Beere, Helen, Yustein, Jason T., DeRenzo, Christopher, Pruett-Miller, Shondra M., Crawford, Jeremy Chase, Krenciute, Giedre, Roberts, Charles W. M., Chi, Hongbo, Green, Douglas R.

Issue&Volume: 2022-06-22

Abstract: The identification of mechanisms to promote memory T (Tmem) cells has important implications for vaccination and anti-cancer immunotherapy1,2,3,4. Using a CRISPR-based screen for negative regulators of Tmem cell generation in vivo5, here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF)6,7. Several components of the cBAF complex are essential for the differentiation of activated CD8+ T cells into T effector (Teff) cells, and their loss promotes Tmem cell formation in vivo. During the first division of activated CD8+ T cells, cBAF and MYC8 frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high MYC and high cBAF display a cell fate trajectory towards Teff cells, whereas those with low MYC and low cBAF preferentially differentiate towards Tmem cells. The cBAF complex and MYC physically interact to establish the chromatin landscape in activated CD8+ T cells. Treatment of naive CD8+ T cells with a putative cBAF inhibitor during the first 48h of activation, before the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves efficacy in a mouse solid tumour model. Our results establish cBAF as a negative determinant of Tmem cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.

DOI: 10.1038/s41586-022-04849-0

Source: https://www.nature.com/articles/s41586-022-04849-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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