Nature immunology · 2025
Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation.
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Feng Xiaogang, Andersson Tilde, Flüchter Pascal, Gschwend Julia, Berest Ivan, Muff Julian L, Lechner Antonie, Gondrand Aurelia, Westermann Patrick, Brander Nina, Carchidi Daniele, De Tenorio Jeshua C, Pan Tianlang, Boehm Ulrich, Klose Christoph S N, Artis David, Messner Christoph B, Leinders-Zufall Trese, Zufall Frank, Schneider Christoph
Аннотация
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.