MIA-reprogramed ILC2s promote enhanced lung allergic inflammation in offspring postnatally and into adulthood

Abstract

Abstract Innate lymphoid cells (ILCs) are a relatively recently identified class of specialized innate-like lymphocytes that are the topic of intense investigation for their role in immune function during homeostasis and disease states. Accumulating evidence suggests that dysregulation of ILC2s and ILC2-derived Type II cytokines plays a critical role in the development of allergic airway hyper-responsiveness and asthma. To test how prenatal inflammation impacts ILC2 establishment, I profiled changes to a committed progenitor to all ILC lineages in the fetal liver (FL). MIA induction during mid-gestation expanded FL Common helper Innate Lymphoid Progenitors, resulting in robustly expanded and hyper-proliferative neonatal ILC2s exhibiting a greater inflammatory phenotype, producing more IL-5 and IL-13 cytokine on a per-cell basis. Hyper-activated ILC2s drove remodeling of the lung immune landscape, with multiple immune cell compartments, including eosinophils and alveolar macrophages, exhibiting expansion during the first two weeks of life in MIA-treated offspring. Surprisingly, levels of IL-33, a potent ILC2 activator, significantly decreased after MIA, and ILC2s were hyper-responsive to IL-33 in ex vivoculture. Single-cell RNA sequencing of neonatal lung ILC2s revealed extensive heterogeneity between MIA and saline litters, including clusters unique to MIA-exposed litters, and transcriptional similar to ILC2 signatures in human asthma patients. Altogether, my data suggests prenatal inflammation imparts lasting changes to lung immunity by perturbing the establishment of committed ILC progenitors in the FL, affecting the generation of neonatal lung ILC2s poised to hyperactively respond to secondary immune activation. NIH/NICHD training grant T32HD007491 The Pew Biomedical Scholars Award