The networks of transcription factors (TFs) that control intestinal-resident memory CD8 + T (T RM ) cells, including multipotency and effector programs, are poorly understood. In this work, we investigated the role of the TF Bcl11b in T RM cells during infection with Listeria monocytogenes using mice with post-activation, conditional deletion of Bcl11b in CD8 + T cells. Conditional deletion of Bcl11b resulted in increased numbers of intestinal T RM cells and their precursors as well as decreased splenic effector and circulating memory cells and precursors. Loss of circulating memory cells was in part due to increased intestinal homing of Bcl11b −/− circulating precursors, with no major alterations in their programs. Bcl11b −/− T RM cells had altered transcriptional programs, with diminished expression of multipotent/multifunctional (MP/MF) program genes, including Tcf7 , and up-regulation of the effector program genes, including Prdm1. Bcl11b also limits the expression of Ahr, another TF with a role in intestinal CD8 + T RM cell differentiation. Deregulation of T RM programs translated into a poor recall response despite T RM cell accumulation in the intestine. Reduced expression of MP/MF program genes in Bcl11b −/− T RM cells was linked to decreased chromatin accessibility and a reduction in activating histone marks at these loci. In contrast, the effector program genes displayed increased activating epigenetic status. These findings demonstrate that Bcl11b is a frontrunner in the tissue residency program of intestinal memory cells upstream of Tcf1 and Blimp1, promoting multipotency and restricting the effector program.

中文翻译：

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Bcl11b 维持多能性并限制肠道驻留记忆 CD8 + T 细胞的效应程序

控制肠道驻留记忆 CD8 的转录因子 (TF) 网络+吨（吨R M) 细胞，包括多能性和效应器程序，人们知之甚少。在这项工作中，我们研究了 TF Bcl11b 在 T 中的作用R M感染期间的细胞李斯特菌使用激活后条件性缺失 CD8 中 Bcl11b 的小鼠+T 细胞。Bcl11b 的条件性缺失导致肠道 T 细胞数量增加R M细胞及其前体细胞以及减少的脾脏效应细胞和循环记忆细胞及其前体细胞。循环记忆细胞的损失部分是由于肠道归巢增加Bcl11b-/- 循环的前体，其程序没有重大改变。Bcl11b-/- 吨R M细胞改变了转录程序，多能/多功能 (MP/MF) 程序基因的表达减少，包括Tcf7，以及效应程序基因的上调，包括PRDM1。Bcl11b 还限制了 Ahr 的表达，Ahr 是另一种在肠道 CD8 中起作用的 TF+吨R M细胞分化。解除对 T 的管制R M尽管 T，程序转化为较差的回忆反应R M细胞在肠道内堆积。Bcl11b 中 MP/MF 程序基因的表达减少-/-吨R M细胞与染色质可及性降低和这些基因座处激活组蛋白标记的减少有关。相反，效应程序基因显示出增加的激活表观遗传状态。这些发现表明 Bcl11b 是 Tcf1 和 Blimp1 上游肠道记忆细胞组织驻留程序的领跑者，可促进多能性并限制效应程序。