Reciprocal changes in CD11c⁺CD11b⁺ and CD11c⁺CD8α⁺ dendritic cell subsets determine protective or permissive immune...

CD11c⁺CD8α⁺ and CD11c⁺CD11b⁺ 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 CD11c⁺CD11b⁺ DCs and increased relative abundance of splenic CD11c⁺CD8α ⁺DCs. During infection, splenic CD11c⁺CD11b⁺ DCs induced Th1 differentiation whereas CD11c⁺CD8α⁺ DCs promoted Th2 differentiation. Additionally, treatment of infected mice with miltefosine as experimental control exhibited host defense allowing the restoration of CD11c⁺CD11b⁺ population and decrease in CD11c⁺CD8α⁺ 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 CD11c⁺CD8α⁺ DCs whereas miltefosine treatment significantly downregulated OX40L expression along with pronounced upregulation of SEMA 4A expression in CD11c⁺CD11b⁺ DCs. SiRNA mediated knockdown of SEMA 4A markedly reduced CD11c⁺CD11b⁺ driven IFN-γ, TNF-α and IL-12 synthesis in miltefosine treated mice whereas functional blocking of OX40L decreased CD11c⁺CD8α⁺ 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 CD11c⁺CD11b⁺ 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.