The study investigates the role of JAK-STAT signaling in maintaining homeostasis in T cells and macrophages. JAK-STAT signaling, beyond its well-known role in immune responses, is found to be a major regulator of immune cell homeostasis. The researchers analyzed the transcription and chromatin accessibility of 12 mouse models, including knockouts of all STAT transcription factors and the TYK2 kinase. They observed baseline JAK-STAT signaling in CD8+ T cells and macrophages of unperturbed mice, which was abrogated in knockouts and unstimulated immune cells deprived of their normal tissue context. The analysis revealed diverse gene-regulatory programs, including effects of STAT2 and IRF9 that were independent of STAT1. The study establishes baseline JAK-STAT activity as a key mediator of homeostasis in unstimulated immune cells, contributing to a poised epigenetic and transcriptional state that prepares these cells for rapid response to immune stimuli. The findings highlight the importance of JAK-STAT signaling in maintaining the functional state of immune cells under homeostatic conditions.The study investigates the role of JAK-STAT signaling in maintaining homeostasis in T cells and macrophages. JAK-STAT signaling, beyond its well-known role in immune responses, is found to be a major regulator of immune cell homeostasis. The researchers analyzed the transcription and chromatin accessibility of 12 mouse models, including knockouts of all STAT transcription factors and the TYK2 kinase. They observed baseline JAK-STAT signaling in CD8+ T cells and macrophages of unperturbed mice, which was abrogated in knockouts and unstimulated immune cells deprived of their normal tissue context. The analysis revealed diverse gene-regulatory programs, including effects of STAT2 and IRF9 that were independent of STAT1. The study establishes baseline JAK-STAT activity as a key mediator of homeostasis in unstimulated immune cells, contributing to a poised epigenetic and transcriptional state that prepares these cells for rapid response to immune stimuli. The findings highlight the importance of JAK-STAT signaling in maintaining the functional state of immune cells under homeostatic conditions.