Distinct roles for IL‐6 and IL‐12p40 in mediating protection against Leishmania donovani and the expansion of IL‐10+ CD4+ T cells

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Abstract
Adoptive dendritic cell (DC) immunotherapy provides a useful experimental tool to evaluate immunoregulation in vivo and has previously been successfully used to enhance host resistance in a variety of experimental models of leishmaniasis. Here, we used this approach to identify IL‐6 and IL‐12p40 as critical cytokines that cooperate to mediate host protection to Leishmania donovani but which act independently to regulate expansion of IL‐10+ CD4+ T cells, shown here for the first time to be associated with this infection. Adoptive transfer of LPS‐activated bone marrow‐derived DC (BMDC) from wild‐type mice was therapeutically beneficial and led to enhanced resistance as measured by spleen parasite burden. In contrast, IL‐6‐ or IL‐12p40‐deficient BMDC had no protective benefit, indicating that production of both cytokines was essential for the therapeutic efficacy of DC. IL‐10 production by CD25– FoxP3– IL‐10+ CD4+ T cells is a strong correlate of disease progression, and BMDC from wild‐type mice inhibited expansion of these cells. Strikingly, IL‐12‐deficient BMDC could also inhibit the expansion of this T cell population whereas IL‐6‐deficient BMDC could not, indicating that IL‐6 played a key role in this aspect of DC function in vivo. Breadth of cytokine production is thus an important factor when considering strategies for DC‐based interventions.