IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children, and severe RSV infection early in life has been associated with asthma development. Using a neonatal mouse model, we have shown that down-regulation of IL-4 receptor a (IL-4R alpha) with antisense oligonucleotides in the lung during neonatal infection protected from RSV immunopathophysiology. Significant down-regulation of IL-4R alpha was observed on pulmonary CD11b + myeloid dendritic cells (mDCs) suggesting a role for IL-4R alpha on mDCs in the immunopathogenesis of neonatal RSV infection. Here, we demonstrated that neonatal CD11b(+) mDCs expressed higher levels of IL-4R alpha than their adult counterparts. Because CD11b(+) mDCs mainly present antigens to CD4(+) T cells, we hypothesized that increased expression of IL-4R alpha on neonatal CD11b(+) mDCs was responsible for Th2 biased RSV immunopathophysiology. Indeed, when IL-4R alpha was selectively deleted from CD11b+ mDCs, the immunopathophysiology typically observed following RSV reinfection was ablated, including Th2 inflammation, airway-mucus hyperproduction, and pulmonary dysfunction. Further, overexpression of IL-4R alpha on adult CD11b+ DCs and their adoptive transfer into adult mice was able to recapitulate the Th2-biased RSV immunopathology typically observed only in neonates infected with RSV. IL-4R alpha levels on CD11c(+) cells were inversely correlated with maturation status of CD11b(+) mDCs upon RSV infection. Our data demonstrate that developmentally regulated IL-4R alpha expression is critical for the maturity of pulmonary CD11b(+) mDCs and the Th2-biased immunopathogenesis of neonatal RSV infection.