Title Functional differences in airway dendritic cells determine susceptibility to IgE-sensitisation Running head Inhaled allergen uptake and IgE-sensitisation

Respiratory IgE-sensitisation to innocuous antigens increases the risk for developing diseases such as allergic asthma. Dendritic cells (DC) residing in the airways orchestrate the immune response following antigen exposure and their ability to sample and present antigens to naïve T cells in airway draining lymph nodes contributes to allergen-specific IgE-sensitisation. In order to characterise inhaled antigen capture and presentation by DC subtypes in vivo, we used an adjuvant-free respiratory sensitisation model using two genetically distinct rat strains, one of which is naturally resistant and the other naturally susceptible to allergic sensitisation. Upon multiple exposures to ovalbumin (OVA), the susceptible strain developed OVA-specific IgE and airway inflammation whereas the resistant strain did not. Using fluorescently tagged OVA and flow cytometry, we demonstrated significant differences in antigen uptake efficiency and presentation associated with either IgE-sensitisation or A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. resistance to allergen exposures in respective strains. We further identified CD4 conventional DC (cDC) as the subset involved in airway antigen sampling in both strains, however CD4 cDC in the susceptible strain were less efficient in OVA sampling and displayed increased MHC-II expression compared to the resistant strain. This was associated with generation of an exaggerated Th2 response and a deficiency of airway regulatory T cells in the susceptible strain. These data suggest that subsets of cDC are able to induce either sensitisation or resistance to inhaled antigens as determined by genetic background, which may provide an underlying basis for genetically determined susceptibility to respiratory allergic sensitisation and IgE production in susceptible individuals.