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<p>Innate immune cells respond rapidly to environmental cues through signal-regulated transcription factors (SRTFs) 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 (ILC2s) 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 accumulation of lung inflammatory ILC2s (iILC2s). Despite elevated STAT4 expression, iILC2s do not acquire type 1 features, such as interferon (IFN)-γ production or T-bet expression and do not respond to IL-12 stimulation. Instead, STAT4 is activated by type I IFNs and supports the maintenance of the iILC2 pool. Transcriptomic analysis of <i>Stat4</i>-deficient ILC2s reveals enhanced type I IFN signaling and impaired proliferation, suggesting that STAT4 functions to antagonize IFN-driven suppression. Our data uncover a novel regulatory axis in which IL-25-induced STAT4 expression equips ILC2s to modulate interferon responses and to prevent aberrant autocrine function of type I IFNs, 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月26日

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  • Giuseppe Pietropaolo,
  • Gianluca Scarno,
  • Arianna Maria Candelotti,
  • Giordana Garzillo,
  • Chiara Di Censo,
  • Giovanna Peruzzi,
  • Cinzia Fionda,
  • Helena Stabile,
  • Francesca Sozio,
  • Chiara D’Aquino,
  • Rosa Molfetta,
  • Fabrizio Leone,
  • Bianca Laura Cinicola,
  • Alessandra Gori,
  • Cecilia Ciancaglini,
  • Silvia Santopolo,
  • Linda Quatrini,
  • Anna Maria Zicari,
  • Han-Yu Shih,
  • Yohei Mikami,
  • Angela Gismondi,
  • Giovanni Bernardini,
  • Katharine C. Hsu,
  • Angela Santoni,
  • Silvano Sozzani,
  • Mattia Laffranchi,
  • Giuseppe Sciumè

摘要

Innate immune cells respond rapidly to environmental cues through signal-regulated transcription factors (SRTFs) 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 (ILC2s) 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 accumulation of lung inflammatory ILC2s (iILC2s). Despite elevated STAT4 expression, iILC2s do not acquire type 1 features, such as interferon (IFN)-γ production or T-bet expression and do not respond to IL-12 stimulation. Instead, STAT4 is activated by type I IFNs and supports the maintenance of the iILC2 pool. Transcriptomic analysis of Stat4-deficient ILC2s reveals enhanced type I IFN signaling and impaired proliferation, suggesting that STAT4 functions to antagonize IFN-driven suppression. Our data uncover a novel regulatory axis in which IL-25-induced STAT4 expression equips ILC2s to modulate interferon responses and to prevent aberrant autocrine function of type I IFNs, 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.