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

Feng, X.; Andersson, T.; Gschwend, J.; Flüchter, P.; Berest, I.; Muff, J. L.; Carchidi, D.; Lechner, A.; de Tenorio, J. C.; Brander, N.; Boehm, U.; Klose, C. S.; Artis, D.; Leinders-Zufall, T.; Zufall, F.; Schneider, C.

doi:10.1101/2024.03.04.583299

bioRxiv · 10.1101/2024.03.04.583299

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

Feng, X.·Andersson, T.·Gschwend, J.·Flüchter, P.·Berest, I.·Muff, J. L.·Carchidi, D.·Lechner, A.·de Tenorio, J. C.·Brander, N.·Boehm, U.·Klose, C. S.·Artis, D.·Leinders-Zufall, T.·Zufall, F.·Schneider, C.

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Abstract

The tuft cell-ILC2 circuit orchestrates rapid type 2 responses upon detecting microbe-derived succinate and luminal helminths. Our findings delineate key mechanistic steps, involving IP3R2 engagement and Ca2+ flux, governing IL-25 production by tuft cells triggered by succinate detection. While IL-17RB plays 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. Suboptimal 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.

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Feng, X., Andersson, T., Gschwend, J., Flüchter, P., Berest, I., Muff, J. L., Carchidi, D., Lechner, A., de Tenorio, J. C., Brander, N., Boehm, U., Klose, C. S., Artis, D., Leinders-Zufall, T., Zufall, F., Schneider, C.. 2024-03-08. Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation. https://doi.org/10.1101/2024.03.04.583299

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