Hyperactivity of the IL33-ST2 axis during postnatal alveolarization increases susceptibility to house dust mite sensitization via skewing of CD11b+ dendritic cells

Early postnatal programming of Th2 polarized memory to house dust mite (HDM) represents a major risk factor for the subsequent development of asthma. We previously reported that CD11b+ conventional dendritic cells (cDCs) is the main HDM presenting DC subset in the lungs. We now show that in neonatal mice this DC subset is very low in absolute numbers and hardly detectable in the lungs. Despite these low numbers sensitization to aero-allergens can take place directly after birth due to excellent HDM-antigen uptake and migratory capacity of the very few neonatal CD11b+ cDCs around. Even more, neonatal CD11b+ cDCs showed a much stronger Th2 skewing activity compared to their adult counterpart. This difference in Th2 skewing capacity was present at birth due to DC intrinsic IL-12p70 deficiency of neonatal CD11b+ cDCs but increased significantly between postnatal day (PND)7 to 21. This age window is characterized by rapid postnatal alveolarization and lung growth and coincided with highly increased baseline and HDM-induced IL-33 levels as well as high numbers of innate lymphoid cells type 2 (ILC2). Due to a direct Th2 skewing effect of these high IL-33 levels on neonatal lung CD11b+ cDCs but also on monocyte derived (Mo)DCs PND14 mice were increased susceptible to HDM sensitization. As a consequence, in vivo blockade of IL-33 via administration of recombinant soluble ST2-receptor during HDM sensitization had a much stronger effect on reducing lung inflammation in PND14 than in PND3 or adult mice.