Febrile-range temperature selectively limits sustained pDC-Derived IFN-α via attenuation of STAT1-Dependent feedback signaling.

Plasmacytoid dendritic cells (pDCs) are specialized sentinels of antiviral immunity and the dominant early source of interferon-α (IFN-α) during viral infection. While pDC-derived IFN-α restricts viral replication and provides a critical third signal for T cell activation, sustained type I interferon (IFN-I) signaling can drive immunopathology, and the physiological mechanisms that constrain this response remain incompletely understood. Here, we identify fever as a conserved host factor that selectively limits IFN-α production by pDCs. We show that febrile-range temperature does not impair early IFN-α induction but instead suppresses sustained IFN-α output in human and mouse pDCs. Mechanistically, elevated temperature attenuates signal transducer and activator of transcription 1 (STAT1) phosphorylation, thereby disrupting the IFN-I-dependent positive feedback loop required for IFN-I amplification following CpG-A stimulation. Pharmacological inhibition of protein phosphatase activity with okadaic acid (OA) restores STAT1 phosphorylation and rescues IFN-α production under febrile conditions. Together, these findings establish fever as a physiological regulator of pDC-derived IFN-I responses and reveal a temperature-dependent mechanism that constrains prolonged IFN-I production to prevent excessive immune activation.