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

Pawan Kumar Yadav, Pragya Chandrakar, Pankaj Sharma, Preeti Vishwakarma, Naveen Parmar, Mrigank Srivastava, Susanta Kar

Vaccine 2020 Jan 10

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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. Copyright © 2019 Elsevier Ltd. All rights reserved.

Citation

Pawan Kumar Yadav, Pragya Chandrakar, Pankaj Sharma, Preeti Vishwakarma, Naveen Parmar, Mrigank Srivastava, Susanta Kar. Reciprocal changes in CD11c+CD11b+ and CD11c+CD8α+ dendritic cell subsets determine protective or permissive immune response in murine experimental VL. Vaccine. 2020 Jan 10;38(2):355-365