Basophils’ IL-4 stifles the function of neonatal DCs and promotes Th2 immunity in newborn mice (CCR4P.212)

Abstract The immune system of newborns displays a deficiency in Th1 lymphocytes but excess Th2 cells leading to poor protective immunity against microbes and prevalence of pediatric allergies. The mechanisms underlying these discrepancies are not fully understood. Herein, we show that upon immunization, neonatal basophils readily produce IL-4 which contributes to the prevalence of Th2 cells in two ways. First, IL-4 is known to directly promote naïve T lymphocytes to differentiate into Th2 cells, but surprisingly, it also binds to the type II IL-4 heteroreceptor (composed of IL-4Rα and IL-13Rα1) on dendritic cells and diminishes their function and IL-12 production. Interestingly, the differentiation program of neonatal T cells proceeds under limited IL-12 which leads to an unusual appearance of the very same type II IL-4 heteroreceptor on Th1 cells which will serve as a death marker. Indeed, during secondary antigen challenge, Th2 cells produce copious IL-4 which triggers apoptosis of the Th1 cells via signaling through the heteroreceptor. While this Th1/Th2 imbalance serves anti-inflammatory roles that allow for embryo engraftment during gestation and maintenance of pregnancy, it severely impacts the capacity of neonates to respond to microbial infections and pediatric vaccination. Potential therapeutics that silence basophils or block IL-4 signaling may be able to restore Th1 responses and allow neonates to combat infections and ultimately reduce childhood mortality.