Foxo1 regulates intestinal tissue–resident memory CD8 T cell biology in an anatomic compartment– and context-specific manner

Tissue-resident memory CD8 T (T_RM) cells serve as a front-line defense against microbial pathogens in barrier and mucosal tissues. Accurately predicting the roles of tissue-specific transcription factors (TFs) that regulate T_RM biology remains a challenge. Here, by applying integrated transcriptomic and epigenomic analyses, we have identified an unexpected role for forkhead box O1 (Foxo1), a TF previously known to regulate circulating memory T cells, in intestinal T_RM biology. Foxo1 repressed the maintenance of early small intestinal intraepithelial T_RM cells in contrast with its actions in sustaining T_RM cells from small intestinal lamina propria and colon and contrary to its broader role in promoting intestinal T_RM cell formation. These findings highlight the emerging concept that the transcriptional regulation of T_RM cells may be more complex and nuanced than previously appreciated and underscore the utility of integrated transcriptomic and epigenomic analyses in reconstructing TF-regulatory networks.