JAK-STAT signaling maintains homeostasis in T cells and macrophages. This study demonstrates that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. Using 12 mouse models, including knockouts of all STAT transcription factors and TYK2 kinase, the researchers investigated JAK-STAT-mediated transcription and chromatin accessibility. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice but was abrogated in knockouts and unstimulated immune cells deprived of their normal tissue context. The study identified diverse gene-regulatory programs, including effects of STAT2 and IRF9 independent of STAT1. The findings reveal a crucial role of JAK-STAT signaling in unstimulated immune cells, contributing to a poised epigenetic and transcriptional state and preparing these cells for rapid response to immune stimuli. The study also highlights the importance of JAK-STAT signaling in maintaining homeostatic conditions, with baseline activity under homeostatic conditions and rapid upregulation of key immune signaling pathways when cells encounter pathogens or other immune stimuli. The results show that JAK-STAT signaling is essential for maintaining the epigenetic potential of immune cells and supports rapid activation without previous chromatin remodeling. The study also identifies the role of JAK-STAT signaling in the regulation of gene expression and chromatin accessibility, with different JAK-STAT proteins controlling distinct gene-regulatory modules. The findings suggest that JAK-STAT signaling is a key regulator of immune cell homeostasis, with baseline activity under homeostatic conditions and the ability to respond rapidly to immune stimuli. The study also shows that the loss of JAK-STAT signaling in the absence of tissue context leads to widespread changes in the transcriptomes and epigenomes of homeostatic immune cells, indicating the importance of the in vivo tissue context in maintaining baseline JAK-STAT signaling. The results highlight the complex and diverse regulatory roles of JAK-STAT signaling in immune cell homeostasis, with different JAK-STAT proteins controlling distinct gene-regulatory modules and contributing to the maintenance of immune cell function under homeostatic conditions.JAK-STAT signaling maintains homeostasis in T cells and macrophages. This study demonstrates that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. Using 12 mouse models, including knockouts of all STAT transcription factors and TYK2 kinase, the researchers investigated JAK-STAT-mediated transcription and chromatin accessibility. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice but was abrogated in knockouts and unstimulated immune cells deprived of their normal tissue context. The study identified diverse gene-regulatory programs, including effects of STAT2 and IRF9 independent of STAT1. The findings reveal a crucial role of JAK-STAT signaling in unstimulated immune cells, contributing to a poised epigenetic and transcriptional state and preparing these cells for rapid response to immune stimuli. The study also highlights the importance of JAK-STAT signaling in maintaining homeostatic conditions, with baseline activity under homeostatic conditions and rapid upregulation of key immune signaling pathways when cells encounter pathogens or other immune stimuli. The results show that JAK-STAT signaling is essential for maintaining the epigenetic potential of immune cells and supports rapid activation without previous chromatin remodeling. The study also identifies the role of JAK-STAT signaling in the regulation of gene expression and chromatin accessibility, with different JAK-STAT proteins controlling distinct gene-regulatory modules. The findings suggest that JAK-STAT signaling is a key regulator of immune cell homeostasis, with baseline activity under homeostatic conditions and the ability to respond rapidly to immune stimuli. The study also shows that the loss of JAK-STAT signaling in the absence of tissue context leads to widespread changes in the transcriptomes and epigenomes of homeostatic immune cells, indicating the importance of the in vivo tissue context in maintaining baseline JAK-STAT signaling. The results highlight the complex and diverse regulatory roles of JAK-STAT signaling in immune cell homeostasis, with different JAK-STAT proteins controlling distinct gene-regulatory modules and contributing to the maintenance of immune cell function under homeostatic conditions.