Tissue-resident memory T cells (T_RM cells) provide protective immunity, but the contributions of specific tissue environments to T_RM cell differentiation and homeostasis are not well understood. In the present study, the diversity of gene expression and genome accessibility by mouse CD8⁺ T_RM cells from distinct organs that responded to viral infection revealed both shared and tissue-specific transcriptional and epigenetic signatures. T_RM cells in the intestine and salivary glands expressed transforming growth factor (TGF)-β-induced genes and were maintained by ongoing TGF-β signaling, whereas those in the fat, kidney and liver were not. Constructing transcriptional–regulatory networks identified the transcriptional repressor Hic1 as a critical regulator of T_RM cell differentiation in the small intestine and showed that Hic1 overexpression enhanced T_RM cell differentiation and protection from infection. Provision of a framework for understanding how CD8⁺ T_RM cells adapt to distinct tissue environments, and identification of tissue-specific transcriptional regulators mediating these adaptations, inform strategies to boost protective memory responses at sites most vulnerable to infection.

组织驻留记忆 T 细胞（T _{RM细胞）提供保护性免疫，但特定组织环境对 T RM}细胞分化和稳态的贡献尚不清楚。在本研究中，来自对病毒感染作出反应的不同器官的小鼠 CD8 ⁺ T _RM细胞的基因表达和基因组可及性的多样性揭示了共享的和组织特异性的转录和表观遗传特征。肠道和唾液腺中的 T RM 细胞表达转化生长因子 (TGF)-β 诱导的基因，并由持续的 TGF-β 信号传导维持，而脂肪、肾脏和肝脏中的 T RM 细胞则不然_。构建转录调节网络确定了转录抑制因子Hic1是小肠T _RM细胞分化的关键调节因子，并表明Hic1过度表达可增强 T _RM细胞分化并防止感染。提供一个框架来了解 CD8 ⁺ T _RM细胞如何适应不同的组织环境，并鉴定介导这些适应的组织特异性转录调节因子，为增强最容易受到感染的部位的保护性记忆反应提供策略。