Inflammatory Dendritic Cells, Regulated by IL-4 Receptor Alpha Signaling, Control Replication, and Dissemination of in Mice

Leishmaniasis is a vector-borne disease caused by parasites. Macrophages are considered the primary parasite host cell, but dendritic cells (DCs) play a critical role in initiating adaptive immunity and controlling infection. Accordingly, our previous study in CD11cIL-4Rα mice, which have impaired IL-4 receptor alpha (IL-4Rα) expression on CD11c cells including DCs, confirmed a protective role for IL-4/IL-13-responsive DCs in replication and dissemination of parasites during cutaneous leishmaniasis. However, it was unclear which DC subset/s was executing this function. To investigate this, we infected CD11cIL-4Rα and control mice with GFP parasites and identified subsets of infected DCs by flow cytometry. Three days after infection, CD11b DCs and CD103 DCs were the main infected DC subsets in the footpad and draining lymph node, respectively and by 4 weeks post-infection, Ly6C and Ly6C CD11b DCs were the main infected DC populations in both the lymph nodes and footpads. Interestingly, Ly6CCD11b inflammatory monocyte-derived DCs but not Ly6CCD11b DCs hosted parasites in the spleen. Importantly, intracellular parasitism was significantly higher in IL-4Rα-deficient DCs. In terms of DC effector function, we found no change in the expression of pattern-recognition receptors (TLR4 and TLR9) nor in expression of the co-stimulatory marker, CD80, but MHCII expression was lower in CD11cIL-4Rα mice at later time-points compared to the controls. Interestingly, in CD11cIL-4Rα mice, which have reduced Th1 responses, CD11b DCs had impaired iNOS production, suggesting that DC IL-4Rα expression and NO production is important for controlling parasite numbers and preventing dissemination. Expression of the alternative activation marker arginase was unchanged in CD11b DCs in CD11IL-4Rα mice compared to littermate controls, but RELM-α was upregulated, suggesting IL-4Rα-independent alternative activation. In summary, parasites may use Ly6CCD11b inflammatory DCs derived from monocytes recruited to infection as "Trojan horses" to migrate to secondary lymphoid organs and peripheral sites, and DC IL-4Rα expression is important for controlling infection.