Reciprocal changes in CD11cCD11b and CD11cCD8α dendritic cell subsets determine protective or permissive immune response in murine experimental VL.

CD11cCD8α and CD11cCD11b dendritic cells are two major subsets of murine splenic CD11c DCs which play a crucial role in T cell priming and shaping Th1/Th2 responses, but their role in the context of experimental visceral leishmaniasis (VL) is poorly understood. Herein, we showed that L. donovani infection in Balb/c mice preferentially decreased the population abundance of CD11cCD11b DCs and increased relative abundance of splenic CD11cCD8α DCs. During infection, splenic CD11cCD11b DCs induced Th1 differentiation whereas CD11cCD8α DCs promoted Th2 differentiation. Additionally, treatment of infected mice with miltefosine as experimental control exhibited host defense allowing the restoration of CD11cCD11b population and decrease in CD11cCD8α subset. Furthermore, reciprocal regulation of immune accessory surface molecules, Sema4A and OX40L critically determined Th1/Th2 response induced by these DC subsets during VL. L. donovani infection significantly induced OX40L expression and slightly downregulated SEMA 4A expression in CD11cCD8α DCs whereas miltefosine treatment significantly downregulated OX40L expression along with pronounced upregulation of SEMA 4A expression in CD11cCD11b DCs. SiRNA mediated knockdown of SEMA 4A markedly reduced CD11cCD11b driven IFN-γ, TNF-α and IL-12 synthesis in miltefosine treated mice whereas functional blocking of OX40L decreased CD11cCD8α induced IL-10, IL-4 and TGF-β synthesis in L. donovani infected group. Vaccination of Balb/c mice with antigen-pulsed + CpG-ODN-activated DC subsets revealed that only antigen-pulsed CD11cCD11b DCs eliminated parasite load in visceral organ and restored protective Th1 cytokine response. Collectively, our results suggest that differential regulation of splenic CD11c subsets by L. donovani is essential for disease progression and specific subtypes may be exploited as prophylactic measures against visceral leishmaniasis.