Bhlhe40 limits early IL-10 production from CD4 + T cells during Plasmodium yoelii 17X infection

The cytokine IL-10 suppresses T-cell-mediated immunity, which is required to control infection with . Consequently, IL-10 can delay the time needed to resolve this infection, leading to a higher parasite burden. While the pathways that lead to IL-10 production by CD4 T cells are well defined, much less is known about the mediators that suppress the expression of this potent anti-inflammatory cytokine. Here, we show that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) contributes to controlling parasite burden in response to infection in mice. Loss of Bhlhe40 expression in mice results in higher expression, higher peak parasitemia, and a delay in parasite clearance. The observed phenotype was not due to defects in T-cell activation and proliferation or the humoral response. Nor was it due to changes in regulatory T-cell numbers. However, blocking IL-10 signaling reversed the outcome in mice, suggesting that excess IL-10 production limits their ability to control the infection properly. In addition to suppressing expression in CD4 T cells, Bhlhe40 can promote expression. Indeed, IFN-γ production by CD4 T cells isolated from the liver was significantly affected by the loss of Bhlhe40. Lastly, Bhlhe40 deletion in T cells resulted in a phenotype similar to that observed in the mice, indicating that Bhlhe40 expression in T cells contributes to the ability of mice to control infection with .