DC-Derived IL-10 Modulates Pro-inflammatory Cytokine Production and Promotes Induction of CD4+IL-10+ Regulatory T Cells during Plasmodium yoelii Infection

Katharina Loevenich, Kristina Ueffing, Simone Abel, Matthias Hose, Kai Matuschewski, Astrid M. Westendorf, Jan Buer, Wiebke Hansen

The cytokine IL-10 plays a crucial role during malaria infection by counteracting the pro-inflammatory immune response. We and others demonstrated that Plasmodium yoelii infection results in enhanced IL-10 production in CD4(+) T cells accompanied by the induction of an immunosuppressive phenotype. However, it is unclear whether this is a direct effect caused by the parasite or an indirect consequence due to T cell activation by IL-10-producing antigen-presenting cells. Here, we demonstrate that CD11c(+)CD11b(+)CD8(-) dendritic cells (DCs) produce elevated levels of IL-10 after P. yoelii infection of BALB/c mice. DC-specific ablation of IL-10 in P. yoelii-infected IL-10(flox/flox)/CD11c-cre mice resulted in increased IFN-γ and TNF-α production with no effect on MHC-II, CD80, or CD86 expression in CD11c(+) DCs. Accordingly, DC-specific ablation of IL-10 exacerbated systemic IFN-γ and IL-12 production without altering P. yoelii blood stage progression. Strikingly, DC-specific inactivation of IL-10 in P. yoelii-infected mice interfered with the induction of IL-10-producing CD4(+) T cells while raising the frequency of IFN-γ-secreting CD4(+) T cells. These results suggest that P. yoelii infection promotes IL-10 production in DCs, which in turn dampens secretion of pro-inflammatory cytokines and supports the induction of CD4(+)IL-10(+) T cells.