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

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.

Leishmania-Infected MHC Class IIhigh Dendritic Cells Polarize CD4+ T Cells toward a Nonprotective T-bet+ IFN-γ+ IL-10+ Phenotype

“…Thus, our data demonstrate a previously proposed association between the frequency of IFN-g + IL-10 + DP CD4 + T cells and susceptibility in leishmaniasis (7,11,32). A recent study underlined, in a resistant model (C57BL/6 mice) of visceral L. donovani infection, also the role of splenic CD11c high DCs in the development of IL-10-producing Th1 cells and disease progression (10). Nevertheless, the differential behavior among infected and bystander DCs and the cytokines involved in CD4 T cell polarization were not explored.…”

“…IL-27 was shown in different infectious models to be crucial in the development of IFN-g + IL-10 + DP CD4 + T cells (8,41,42). More recently, a correlative presence of IL-27-producing splenic DCs and DP CD4 + T polarization in vivo was shown, although a direct link was not proved (10). In our DC-L. infantum experimental model, we failed to confirm this link.…”

“…In addition, MHC II int dermal monocyte-derived DCs (44) or even resident MHC II low lymphoid tissue DCs (45) were suggested to play a preponderant role in the development of T cell immunity against pathogens. Once in the spleen, Leishmania will contact with DCs expressing high levels of cell-surface MHC II molecules (10,46). In this article, we demonstrated that only infected MHC II high DCs, both of in vitro or ex vivo origin, were capable of inducing the polarization of CD4 + T cells toward a DP phenotype.…”

“…and control Toxoplasma spp. or Plasmodium-induced immunopathology (7)(8)(9)(10). In an experimental resistant murine model of VL, a CD11c high dendritic cell (DC)-driven expansion and/or maintenance of IL-10-producing Th1 was observed in the passage to chronicity (10,11).…”

“…or Plasmodium-induced immunopathology (7)(8)(9)(10). In an experimental resistant murine model of VL, a CD11c high dendritic cell (DC)-driven expansion and/or maintenance of IL-10-producing Th1 was observed in the passage to chronicity (10,11). These IFN-g + IL-10 + double-positive cells were found to arise from IFNg-producing Th1 cells and are often observed in both pathogen- specific and nonspecific T cell clones, which argue in favor of nonspecific bystander T cell activation (9).…”