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.] Newborns are highly susceptible to microbial infections and allergic reactions. This susceptibility is due to a lack of Th1 cells and an excess of Th2 cells. However, the mechanism underlying this Th1/Th2 imbalance has not been clearly elucidated. Although Th1 cells are present in the primary response, they up-regulate the IL-13R[alpha]1 chain. Consequently, IL-13R[alpha]1 can bind with IL-4R[alpha] to form a heteroreceptor through which IL-4 from Th2 cells can signal and cause the death of Th1 cells. Formation of this death receptor is influenced by the neonatal environment and intrinsic T cell factors. Here we show that limited IL12 in the neonatal environment supports IL-13Ralpha1 up-regulation and Th1 cell death. This lack of IL-12 is due to a low frequency of CD8[alpha]+CD4- DCs, the main producer of IL-12. However, by day 6 after birth, this DC subset reaches a significant accumulation and produces sufficient IL-12 that can downregulate IL-13R[alpha]1 and restore Th1 responses. Interestingly, T cells also contribute to the Th2 bias of neonatal immunity as adult T cells do not up-regulate IL-13Ralpha1 when primed within the neonatal environment. In fact, by 8 days after birth T cells do not up-regulate IL-13R[alpha]1 after antigen stimulation as they express the IL-12R[beta]2 chain which serves as a compensation mechanism that prevents death. Finally, IL-4 induced death appears to be due to activation of the extrinsic and intrinsic apoptosis pathways as neonatal Th1 cells have increased FasL and Bim expression. Together these results could have direct impact on pediatric vaccine development.--From public.pdf