A critical period of innate-immune development: Fetal origins of allergic asthma susceptibility

Abstract

Abstract Our lab previously identified a developmentally-restricted hematopoietic stem cell (drHSC) that only exists during fetal development and specifically gives rise to innate-like lymphocytes that persist across the lifespan. The identification of a developmentally-limited cell of origin for innate-like immune cells defines a “critical window” for immune development, in which the phenotype of the developing immune system can be shaped via extrinsic inputs. To test how perturbation during this critical window drives immune dysfunction, we examined underlying changes to innate lymphoid cells (ILCs) in the lung. ILCs are a recently identified family of fetal-derived innate-like lymphocytes that mimic the adaptive T-helper arm of our immune system. In the lung, type-2 innate lymphoid cells (ILC2s) produce IL5 and IL13, cytokines important for eosinophil recruitment, activation and goblet cell hyperplasia during allergic airway inflammation. Surprisingly, a single low-dose injection of poly (i:c) at mid-gestation robustly increased proliferative capacity and cellularity of lung ILC2s in offspring at postnatal day (P)9 and P14, respectively, concomitant with drHSC and common-helper innate lymphoid progenitor (ChILP) cell expansion during fetal development. Additionally, in poly (i:c) perturbed offspring, lung ILC2s exhibited heightened IL5 and IL13 production upon in-vitro stimulation with PMA and ionomycin. Ongoing experiments will examine how perturbation of transient progenitors during fetal development may impact the ChILP cell immune trajectory, altering the establishment and function of neonatal lung ILC2s, and ultimately contributing to allergic asthma susceptibility into adulthood.