Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8⁺ T cells and macrophages of unperturbed mice—but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse gene-regulatory programs, including effects of STAT2 and IRF9 that were independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wild-type mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcriptional state and helps prepare these cells for rapid response to immune stimuli.

免疫细胞需要在一生中保持持续的警觉状态。然而，人们对控制动态而脆弱的平衡（即稳态）的调节过程知之甚少。在这里，我们证明 JAK-STAT 信号传导除了在免疫反应中的作用之外，还是免疫细胞稳态的主要调节因子。我们研究了 12 种小鼠模型中 JAK-STAT 介导的转录和染色质可及性，包括所有 STAT 转录因子和 TYK2 激酶的敲除。在未受干扰的小鼠的 CD8 ⁺ T 细胞和巨噬细胞中检测到基线 JAK-STAT 信号传导，但在基因敲除和被剥夺正常组织环境的未刺激免疫细胞中被消除。我们观察到了不同的基因调控程序，包括独立于 STAT1 的 STAT2 和 IRF9 的影响。总之，我们对 JAK-STAT 突变型和野生型小鼠的大规模数据集和综合分析揭示了 JAK-STAT 信号在未刺激的免疫细胞中的关键作用，它有助于稳定的表观遗传和转录状态，并帮助准备这些细胞对免疫刺激做出快速反应。