Trained ILC2 prevent IL-17-associated lung injury during helminth infection through a serotonin-dependent mechanism

Femoe, U. M.; Musaigwa, F.; Nicolis, I.; Hung, L.-Y.; Napuri, C.; Uzoije, C.; Rossi, H. L.; Lin, C.; Winters, H.; Reed, D. R.; Herbert, D. R.; Inclan-Rico, J. M.

doi:10.1101/2025.11.03.683154

bioRxiv · 10.1101/2025.11.03.683154

Trained ILC2 prevent IL-17-associated lung injury during helminth infection through a serotonin-dependent mechanism

Femoe, U. M.·Musaigwa, F.·Nicolis, I.·Hung, L.-Y.·Napuri, C.·Uzoije, C.·Rossi, H. L.·Lin, C.·Winters, H.·Reed, D. R.·Herbert, D. R.·Inclan-Rico, J. M.

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Abstract

Type 2 cytokine release promotes wound healing and helminth clearance, but it remains unclear whether group 2 innate lymphocytes (ILC2s) and T-helper 2 cells (TH2) cells have functionally distinct roles during anamnestic immunity. This study demonstrates that ILC2 can block re-infection and limit tissue injury caused by the helminth Nippostrongylus brasiliensis (Nb). TH2 cells were necessary during initial antigen encounter but dispensable for pathogen clearance and lung repair after ILC2 priming. Upon re-infection, trained ILC2 selectively blocked interleukin (IL)-17+ {gamma}{delta}T cell expansion and infection-induced lung injury through an Amphiregulin (Areg)-independent mechanism. Trained ILC2s had a distinct metabolic gene expression profile marked by elevated tryptophan hydroxylase 1(Tph1) and pulmonary serotonin levels were largely ILC2-dependent. Surprisingly, serotonin prevented IL-17-associated lung hemorrhage irrespective of parasite load. We propose that TH2-ILC2 interactions drive pathogen control, but ILC2 distinctly control lung tissue repair through serotonin.

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Femoe, U. M., Musaigwa, F., Nicolis, I., Hung, L.-Y., Napuri, C., Uzoije, C., Rossi, H. L., Lin, C., Winters, H., Reed, D. R., Herbert, D. R., Inclan-Rico, J. M.. 2025-11-04. Trained ILC2 prevent IL-17-associated lung injury during helminth infection through a serotonin-dependent mechanism. https://doi.org/10.1101/2025.11.03.683154

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