Dendritic cells, IL-12Rbeta2, and IL-13Ralpha1 signaling: the battle for control of neonatal immunity

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Upon re-challenge with antigen, newborns develop predominantly Th2 responses, leaving them vulnerable to microbial infections. While Th1 cells develop in the primary response alongside their Th2 counterparts, only Th1 cells up-regulate IL-13Rα1. This chain then associates with the IL-4Rα chain, forming an IL-13Rα1/ IL-4Rα type II receptor. Consequently, IL-4 from Th2 cells can signal through this receptor, leading to the death of Th1 cells and ultimately the Th2 bias of neonatal immunity. Regulation of this “death” receptor is dependent upon both the innate and adaptive immune system. Initially, CD8α+CD4- DCs are few in number and produce little IL-12, resulting in IL-13Rα1 up-regulation on Th1 cells. However, by day 6 after postpartum, this DC subset increases in frequency and produces sufficient IL-12 to down-regulate IL-13Rα1, diminish apoptosis, and restore Th1 responses. Additionally, IL-13Rα1 expression is also controlled by an intrinsic T cell factor as evident by the fact that adult T cells do not up-regulate IL-13Rα1 when primed within the neonatal environment where IL-12 is scarce. This factor lies in the spontaneous up-regulation of IL-12Rβ2 on naïve T cells by 8 days postpartum which can counter IL-13Rα1 expression upon antigen exposure to and rescue Th1 responses. Futhermore, signaling through IL-13Rα1 by IL-4 leads to increased expression of FasL and the pro-apoptotic molecule Bim in neonatal Th1 cells, leading to their death. Collectively, many factors contribute to the Th2 bias of neonatal immunity and can be exploited to generate better pediatric vaccines.