Characterizing a “critical window” of immune development: how perturbation of developmental hematopoiesis shapes immune function and susceptibility to disease in offspring

Abstract

Abstract During development, fetal hematopoietic stem cells (HSCs) are responsible for the production of “unconventional” innate-like immune cells that persist across the lifespan and contribute to adult immunity. Dysregulation of fetal-derived immune cells contributes to pathogenesis in a variety of immune tolerance disorders, including allergy and asthma; however, the cellular and molecular mechanisms driving pathogenesis are unknown. Using a fate-mapping approach, we have previously identified a developmentally-restricted HSC (drHSC) that is lymphoidbiased and specifically gives rise to innate-like lymphocytes. The drHSC exists during perinatal development but disappears postnatally and does not persist into adulthood under homeostatic conditions. Our discovery of a transient cell-of-origin for a specialized component of adult immunity defines a “critical window” of immune development, during which phenotype can be shaped by extrinsic inputs in early life. We have validated the existence of this critical window of immune development by demonstrating that maternal immune perturbation with a single low-dose injection of poly(I:C) at mid-gestation induces lasting changes to the both hematopoiesis and immunity in offspring. Specifically, maternal immune perturbation causes expansion of the drHSC population in offspring and its inappropriate persistence into adulthood. Furthermore, inappropriate expansion and persistence of the drHSC population consequently results in parallel expansion of innate-like lymphocytes, thereby altering immune landscape and function in offspring. Ongoing work investigates the consequences of developmental perturbation on susceptibility to immune dysfunction, including asthma.