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

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 (T_H2) cells have functionally distinct roles during anamnestic immunity. This study demonstrates that ILC2 can prevent re-infection and limit tissue injury caused by the helminth Nippostrongylus brasiliensis (Nb). T_H2 cells were necessary during initial antigen encounter but dispensable for early pathogen clearance and lung repair after ILC2 priming. Upon re-infection, trained ILC2 selectively blocked interleukin (IL)-17+ γδT 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 T_H2-ILC2 interactions drive pathogen control, but ILC2 distinctly control lung tissue repair through serotonin.

Keywords: Helminth; Lung; Serotonin; Tissue repair; Type 2 immunity; trained ILC2.