STAT1 maintains naïve CD8+ T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis.

Naive CD8+ T cell quiescence is maintained at a steady state. Although this state of quiescence involves various cell-intrinsic and cell-extrinsic regulators, the mechanisms underlying this regulation remain incompletely understood. Here, we found that signal transducer and activator of transcription 1 (STAT1), a key transcription factor downstream of interferon receptor (IFNR) signaling, plays a cell-intrinsic role in maintaining naive CD8+ T cell quiescence. STAT1-deficient mice showed enhanced proliferation of peripheral naive CD8+ T cells, which resulted in an abnormal increase in the number of CD44hi memory/activated phenotype cells and an enlargement of secondary lymphoid tissues. This phenomenon was not observed in IFNR-deficient mice but was paradoxically dependent on type I interferon and its alternative signaling pathway via the STAT4–RagD–lysosomal mTORC1 axis. Collectively, these findings underline the importance of STAT1 in regulating the homeostasis of peripheral naive CD8+ T cells by suppressing their responsiveness to homeostatic cues at a steady state.