Comparison of the Abilities of IL-10- and Retinoic Acid- Differentiated Dendritic Cells to Induce Allergen Tolerance in a Mouse Model of Asthma
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Dendritic cells (DCs) in different compartments can affect tolerance via distinct mechanisms. Thus, retinoid acid (RA) and integrins expressed by CD103+ dendritic cells in the gut play important roles in regional regulatory T cell induction and trafficking, while IL-10 expression by lung-associated tolerogenic dendritic cells is integral to tolerance in that compartment. Whether RA- and IL-10-differentiated DC (DCRA and DC10, respectively) can reciprocally induce tolerance in either compartment remains largely unexplored. We have shown that DC10 induce asthma tolerance in part by activating CD25+Foxp3+ Treg, but also by recruiting other cells (e.g., endogenous pulmonary DC) into an infectious tolerance pathway. Herein we began to assess whether DCRA can be equally tolerogenic, and whether they employ similar mechanisms, in an OVA/alum mouse model of asthma. On FACS analysis, we found that DCRA expressed significantly higher levels of CD40, CD86 and MHC II than DC10 (i.e., at levels equivalent to fully mature DC). DCRA secreted higher levels of TGF-β1 and IL-27 than DC10, but equivalent levels of IL-10. DCRA and DC10 suppressed in vitro Th2 response, but DCRA were more effective than DC10 at suppressing proliferation. Both DCRA and DC10 increased expression of Foxp3+ on effector T cells. DCRA promoted little expansion of Foxp3+ T cells. In contrast, DC10 promoted expansion of Foxp3+ T cells. Treatment of asthmatic mice with DC10 and DCRA reduced airway hyperresponsiveness and serum allergen-specific IgE and IgG1 levels. We previously showed that DC10-induced tolerance is critically dependent on their expression of IL-10. The results of this study showed that both DCRA and DC10 induce tolerance in asthmatic mice through different mechanisms.
DegreeMaster of Science (M.Sc.)
SupervisorGordon, John R.
CommitteeHill, Janet; Gerdts, Volker; Griebel, Philip; Xiang, Jim
Copyright DateOctober 2014
IL-10, Retinoic Acid, Dendritic Cells, Tolerance, Asthma