Prenatal inflammation remodels lung immunity and function by programming ILC2 hyperactivation.

Here, we examine how prenatal inflammation shapes tissue function and immunity in the lung by reprogramming tissue-resident immune cells from early development. Maternal, but not fetal, type I interferon-mediated inflammation provokes expansion and hyperactivation of group 2 innate lymphoid cells (ILC2s) seeding the developing lung. Hyperactivated ILC2s produce increased IL-5 and IL-13 and are associated with acute Th2 bias, decreased Tregs, and persistent lung eosinophilia into adulthood. ILC2 hyperactivation is recapitulated by adoptive transfer of fetal liver precursors following prenatal inflammation, indicative of developmental programming at the fetal progenitor level. Reprogrammed ILC2 hyperactivation and subsequent lung immune remodeling, including persistent eosinophilia, is concomitant with worsened histopathology and increased airway dysfunction equivalent to papain exposure, indicating increased asthma susceptibility in offspring. Our data elucidate a mechanism by which early-life inflammation results in increased asthma susceptibility in the presence of hyperactivated ILC2s that drive persistent changes to lung immunity during perinatal development. [Display omitted] • Prenatal inflammation induces expanded and hyperactivated lung ILC2s in offspring • Prenatal inflammation programs ILC2 hyperactivation from fetal progenitors • ILC2 hyperactivation is concomitant with remodeling of the lung immune landscape • Hyperactivated ILC2s promote persistent eosinophilia and lung dysfunction in adults López et al. report that prenatal inflammation induces lung ILC2 expansion and hyperactivation programmed from a fetal hematopoietic progenitor. Increased IL-5 and IL-13 production from hyperactivated ILC2s was associated with remodeled lung immunity, including sustained eosinophilia that promoted lung dysfunction and histopathology in adulthood. [ABSTRACT FROM AUTHOR]