Perturbation of Developmental Hematopoiesis Shapes Lung ILC2 Immune Memory

Abstract

Abstract Our lab has previously identified a developmentally-restricted hematopoietic stem cell (drHSC) that only exists in the perinatal period and specifically gives rise to innate-like lymphocytes. The identification of a developmentally-limited cell of origin for innate-like immune cells that persist across the lifespan defines a “critical window” for immune development, in which the phenotype of the adult immune system can be shaped by extrinsic inputs. To test how developmental perturbation during this critical window drives immune dysfunction, we examined underlying changes to innate-like immune cells in the lung and susceptibility to airway dysfunction following maternal immune stimulation. Lung type-2 innate lymphoid cells (ILC2s) are recognized as potent producers of IL5 and IL13, cytokines important for eosinophil recruitment, activation and goblet cell hyperplasia during allergic airway inflammation. Surprisingly, maternal immune stimulation via a single low-dose injection of poly (i:c) at mid-gestation robustly increased the cellularity of lung ILC2s in offspring at postnatal day 14, concomitant with drHSC and ILC2 progenitor expansion during fetal development. Additionally, lung ILC2s exhibited heightened IL5 and IL13 production upon in-vitro stimulation with PMA and ionomycin in poly (i:c) perturbed offspring. Ongoing experiments examine how altered ILC2 functionality, as a result of developmental perturbation, underlie susceptibility to allergic asthma in response to secondary house-dust mite immune stimulation. Together, our data suggest perinatal immune perturbation may contribute to allergic asthma susceptibility by altering drHSC establishment and training lung ILC2 “innate immune memory”.