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

Leishmaniasis is a vector-borne disease caused by Leishmania parasites. Macrophages are considered the primary parasite host cell, but dendritic cells (DCs) play a critical role in initiating adaptive immunity and controlling Leishmania infection. Accordingly, our previous study in CD11c(cre)IL-4R alpha(-/lox) mice, which have impaired IL-4 receptor alpha (IL-4R alpha) 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 CD11c(cre)IL-4R alpha(-/lox) and control mice with L. major 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, Ly6C(+)CD11b(+) inflammatory monocyte-derived DCs but not Ly6C(-)CD11b(+) DCs hosted parasites in the spleen. Importantly, intracellular parasitism was significantly higher in IL-4R alpha-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 CD11c(cre)IL-4R alpha(-/lox) mice at later time-points compared to the controls. Interestingly, in CD11c(cre)IL-4R alpha(-/lox) mice, which have reduced Th1 responses, CD11b(+) DCs had impaired iNOS production, suggesting that DC IL-4R alpha 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 CD11(cre)IL-4R alpha(-/lox) mice compared to littermate controls, but RELM-alpha was upregulated, suggesting IL-4R alpha-independent alternative activation. In summary, L. major parasites may use Ly6C(+)CD11b(+) inflammatory DCs derived from monocytes recruited to infection as "Trojan horses" to migrate to secondary lymphoid organs and peripheral sites, and DC IL-4R alpha expression is important for controlling infection.