Tissue-resident memory CD8+ T cells possess unique transcriptional, epigenetic and functional adaptations to different tissue environments [CAPvsColl RNA-seq]

CD8+ memory T cells are critical components of protective immunity to intracellular pathogens and tumors. While many memory CD8+ T cells recirculate throughout the body, others remain lodged in tissues and guard common sites of pathogen entry. Contributions of the specific tissue environment to tissue-resident memory T cell (Trm) differentiation and homeostasis have been implicated but are not well understood. Here, we define the diversity of gene expression and genome accessibility by mouse CD8+ Trm populations in distinct organs and identify molecules critical for Trm generated in response to acute viral infection. We find that CD8+ TRM across different tissues possess both shared and tissue-specific transcriptional and epigenetic signatures. Notably, Trm in the intestine and salivary gland express TGFb-induced genes and are maintained by ongoing TGFb signaling while those in the fat, kidney, and liver are not. By constructing transcriptional-regulatory networks for each Trm population, we identify the repressor Hic1 as a critical regulator of Trm differentiation, particularly for Trm of the small intestine. This study provides a framework for understanding how Trm adapt to distinct tissue environments and identifies tissue-specific transcriptional regulators that mediate these adaptations, informing strategies to enhance protective memory responses at the sites most vulnerable to infection. Overall design: RNA-sequencing of P14 CD8+ T cells (specific for LCMV-Armstrong) isolated from the Spleen, Blood, IEL, Kidney, Salivary Gland, and Liver 32 days after intial infection.