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<p>The tuft cell–group 2 innate lymphoid cell (ILC2) circuit orchestrates rapid type 2 responses upon detecting microbially derived succinate and luminal helminths. Our findings delineate key mechanistic steps involving IP3R2 engagement and Ca<sup>2+</sup> flux, governing interleukin-25 (IL-25) production by tuft cells triggered by succinate detection. While IL-17RB has a pivotal intrinsic role in ILC2 activation, it exerts a regulatory function in tuft cells. Tuft cells exhibit constitutive <i>Il25</i> expression, placing them in an anticipatory state that facilitates rapid production of IL-25 protein for ILC2 activation. Tuft cell IL-17RB is crucial for restraining IL-25 bioavailability, preventing excessive tonic ILC2 stimulation due to basal <i>Il25</i> expression. Supraoptimal ILC2 stimulation by IL-25 resulting from tuft cell <i>Il17rb</i> deficiency or prolonged succinate exposure induces a state of hypoproliferation in ILC2s, also observed in chronic helminth infection. Our study offers critical insights into the regulatory dynamics of IL-25 in this circuit, highlighting the delicate tuning required for responses to diverse luminal states.</p>

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Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月12日

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  • Xiaogang Feng,
  • Tilde Andersson,
  • Pascal Flüchter,
  • Julia Gschwend,
  • Ivan Berest,
  • Julian L. Muff,
  • Antonie Lechner,
  • Aurelia Gondrand,
  • Patrick Westermann,
  • Nina Brander,
  • Daniele Carchidi,
  • Jeshua C. De Tenorio,
  • Tianlang Pan,
  • Ulrich Boehm,
  • Christoph S. N. Klose,
  • David Artis,
  • Christoph B. Messner,
  • Trese Leinders-Zufall,
  • Frank Zufall,
  • Christoph Schneider

摘要

The tuft cell–group 2 innate lymphoid cell (ILC2) circuit orchestrates rapid type 2 responses upon detecting microbially derived succinate and luminal helminths. Our findings delineate key mechanistic steps involving IP3R2 engagement and Ca2+ flux, governing interleukin-25 (IL-25) production by tuft cells triggered by succinate detection. While IL-17RB has a pivotal intrinsic role in ILC2 activation, it exerts a regulatory function in tuft cells. Tuft cells exhibit constitutive Il25 expression, placing them in an anticipatory state that facilitates rapid production of IL-25 protein for ILC2 activation. Tuft cell IL-17RB is crucial for restraining IL-25 bioavailability, preventing excessive tonic ILC2 stimulation due to basal Il25 expression. Supraoptimal ILC2 stimulation by IL-25 resulting from tuft cell Il17rb deficiency or prolonged succinate exposure induces a state of hypoproliferation in ILC2s, also observed in chronic helminth infection. Our study offers critical insights into the regulatory dynamics of IL-25 in this circuit, highlighting the delicate tuning required for responses to diverse luminal states.