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

Transcriptional regulation of diverse aspects of tissue-resident CD8 memory T cells (TRM) biology is nuanced and context-specific. Transcription factors (TF) that orchestrate TRM formation and maintenance are distinct between anatomic compartments, and predicting the roles of TF on TRM biology is challenging. Here, we applied the Taiji algorithm to map TF networks and identify Forkhead Box protein 01 (Foxo1) as differentially invested in intestinal TRM TF networks. Loss of Foxo1 in established TRM resulted in a survival advantage for small intestinal intraepithelial layer (siIEL) TRM compared with other intestinal compartments. SiIEL TRM were uniquely able to maintain expression of proliferative and anti-apoptotic cellular programs in the absence of Foxo1. This advantage was lost upon blockade of integrin αE (Itgae/CD103). These findings suggest that the TF networks maintaining siIEL TRM exhibit redundancy and highlight an underappreciated role of integrin signaling in TRM biology outside of tissue-retention.