The identification of mechanisms to promote memory T (T_mem) cells has important implications for vaccination and anti-cancer immunotherapy^1,2,3,4. Using a CRISPR-based screen for negative regulators of T_mem 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 (T_eff) cells, and their loss promotes T_mem 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 T_eff cells, whereas those with low MYC and low cBAF preferentially differentiate towards T_mem 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 48 h 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 T_mem cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.

识别促进记忆 T (T _mem ) 细胞的机制对疫苗接种和抗癌免疫疗法^1,2,3,4具有重要意义。使用基于 CRISPR 的屏幕来筛选体内T _mem细胞生成的负调节剂⁵，在这里我们确定了哺乳动物典型 BRG1/BRM 相关因子 (cBAF) ^6,7的多个成分。cBAF 复合物的几个成分对于活化的 CD8 ⁺ T 细胞分化为 T 效应 (T _eff ) 细胞至关重要，它们的缺失促进了体内T _{mem细胞的形成。}在活化的 CD8 ⁺ T 细胞的第一次分裂过程中，cBAF 和 MYC ⁸经常不对称地共同分配给两个子细胞。具有高 MYC 和高 cBAF 的子细胞显示出朝向 T _eff细胞的细胞命运轨迹，而具有低 MYC 和低 cBAF 的子细胞优先分化为 T _mem细胞。cBAF 复合体和 MYC 物理相互作用以在活化的 CD8 ⁺ T 细胞中建立染色质景观。在嵌合抗原受体 T (CAR-T) 细胞生成之前，在激活的最初 48 小时内，使用推定的 cBAF 抑制剂处理初始 CD8 ⁺ T 细胞，可显着提高小鼠实体瘤模型的疗效。我们的结果将 cBAF 确定为 T _{mem的负决定因素}细胞命运，并表明在 T 细胞分化早期操纵 cBAF 可以改善癌症免疫治疗。