IL-10-Producing Th1 Cells and Disease Progression Are Regulated by Distinct CD11c+ Cell Populations during Visceral Leishmaniasis

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Abstract
IL-10 is a critical regulatory cytokine involved in the pathogenesis of visceral leishmaniasis caused by Leishmania donovani and clinical and experimental data indicate that disease progression is associated with expanded numbers of CD4+ IFNγ+ T cells committed to IL-10 production. Here, combining conditional cell-specific depletion with adoptive transfer, we demonstrate that only conventional CD11chi DCs that produce both IL-10 and IL-27 are capable of inducing IL-10-producing Th1 cells in vivo. In contrast, CD11chi as well as CD11cint/lo cells isolated from infected mice were capable of reversing the host protective effect of diphtheria toxin-mediated CD11c+ cell depletion. This was reflected by increased splenomegaly, inhibition of NO production and increased parasite burden. Thus during chronic infection, multiple CD11c+ cell populations can actively suppress host resistance and enhance immunopathology, through mechanisms that do not necessarily involve IL-10-producing Th1 cells. Dendritic cells are well known as myeloid cells that bridge innate and adaptive immunity, and play an important role in the induction of cell-mediated immunity to a variety of pathogens. However, very little is known about the function of dendritic cells after infection has become established. In this study, we have examined the role of dendritic cells during the later phases of experimental visceral leishmaniasis, caused by infection with Leishmania donovani. We show for the first time that dendritic cells are responsible for promoting the development of splenic pathology, and that their removal during established infection leads to improved host resistance. Furthermore, our studies provide the first formal evidence in vivo that dendritic cells making IL-27 can induce production of the regulatory cytokine IL-10 by effector Th1-like CD4+ T cells. Surprisingly, we also found that other populations of CD11c+ cells were able to induce pathology and suppress host resistance, yet did not stimulate IL-10 production in CD4+ T cells, suggesting that the latter T cell population may not play an essential role in disease progression. Our studies provide new insights into dendritic cell function in chronic parasite infection and suggest potential new avenues for immunotherapy against visceral leishmaniasis.

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