3001 – PRENATAL IMMUNE PERTURBATION ALTERS FETAL HEMATOPOIESIS AND SHAPES OFFSPRING IMMUNITY

During development, transient fetal hematopoietic stem cells (HSCs) are responsible for the production of "unconventional" innate-like immune cells that contribute to adult immunity. Whereas dysregulation of fetal-derived immune cells contributes to pathogenesis in a variety of immune tolerance disorders, the cellular and molecular drivers of pathogenesis are unknown. We have previously identified a transient developmentally-restricted HSC (drHSC) that specifically gives rise to innate-like lymphocytes during the perinatal period1. Under homeostatic conditions, the drHSC disappears postnatally, but its innate-like lymphocyte progeny persist into adulthood. Our discovery of a transient cell-of-origin for a specialized component of adult immunity underscores a “critical window” of immune development, during which phenotype of the adult immune system can be shaped by extrinsic inputs in early life. Here, we tested how developmental perturbation induced in utero by a single low-dose injection of poly(I:C) at mid-gestation drives both immediate and lasting changes to hematopoiesis and immunity in offspring. In utero perturbation disrupted the entrance of fetal HSCs into quiescence, causing disproportionate expansion of drHSCs, and a resultant shift in multipotent progenitor output. Postnatally, we observed sustained expansion and inappropriate persistence of the drHSC population into adulthood. These fundamental changes to the postnatal HSC compartment resulted in parallel expansion and hyperactivation of innate-like lymphocytes, thereby altering immune landscape and function in offspring. Our work validates the existence of a critical window of immune development by revealing how early perturbation of distinct fetal HSCs can drive long-term changes to immunity and disease susceptibility in offspring.