STAT4 drives optimal expansion and transcriptional repression of type I interferon pathway in inflammatory ILC2

Innate immune cells respond rapidly to environmental cues through signal-regulated transcription factors (SRTF) that sense changes in the tissue microenvironment. Signal Transducer and Activator of Transcription (STAT) proteins are critical regulators of cytokine signaling and determine polarized immune responses. Herein, we reveal that activated type 2 innate lymphocytes (ILC2) express STAT4, a SRTF canonically linked to type 1 immunity. STAT4 expression is induced in ILC2s upon activation by the alarmin IL-25 and linked with generation of inflammatory ILC2s (iILC2s), a subset characterized by a mixed type 2/type 3 cytokine profile. Despite elevated STAT4 expression, iILC2s do not acquire type 1 features, such as IFN-g production or T-bet expression and do not respond to IL-12 stimulation. Instead, STAT4 is activated downstream of type I interferons and supports the maintenance of the iILC2 pool. Transcriptomic analysis of Stat4-deficient ILC2s reveals enhanced type I interferon signaling and impaired proliferation, suggesting that STAT4 functions to antagonize interferon-driven suppression. Our data uncover a novel regulatory axis in which IL-25-induced STAT4 expression equips ILC2s to modulate interferon responses, thus sustaining inflammatory effector populations during immune activation. These findings broaden the understanding of ILC2 activation and suggest new avenues for modulating innate lymphocytes in inflammatory diseases.