Tissue-resident memory CD8⁺ T cells possess unique transcriptional, epigenetic and functional adaptations to...

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.