Strong Impact of CD4+Foxp3+ Regulatory T Cells and Limited Effect of T Cell-Derived IL-10 on Pathogen Clearance during Plasmodium yoelii Infection

Abstract

It is well established that CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a crucial role in the course of different infectious diseases. However, contradictory results have been published regarding to malaria infection. In this study, we report that specific ablation of Foxp3+ Tregs in Plasmodium yoelii-infected DEREG-BALB/c mice leads to an increase in T cell activation accompanied by a significant decrease in parasitemia. To better understand how Foxp3+ Tregs orchestrate this phenotype, we used microarrays to analyze CD4+CD25+Foxp3+ Tregs and CD4+CD25−Foxp3− T cells in the course of P. yoelii infection. Using this approach we identified genes specifically upregulated in CD4+CD25+Foxp3+ Tregs in the course of infection, such as G-protein-coupled receptor 83 and Socs2. This analysis also revealed that both CD4+CD25+Foxp3+ Tregs and CD4+CD25−Foxp3− T cells upregulate CTLA-4, granzyme B, and, more strikingly, IL-10 during acute blood infection. Therefore, we aimed to define the function of T cell-derived IL-10 in this context by Cre/loxP-mediated selective conditional inactivation of the IL-10 gene in T cells. Unexpectedly, IL-10 ablation in T cells exerts only a minor effect on parasite clearance, even though CD8+ T cells are more strongly activated, the production of IFN-γ and TNF-α by CD4+CD25- T cells is increased, and the suppressive activity of CD4+CD25+ Tregs is reduced upon infection. In summary, these results suggest that CD4+Foxp3+ Tregs modulate the course of P. yoelii infection in BALB/c mice. Moreover, CD4+ T cell-derived IL-10 affects T effector function and Treg activity, but has only a limited direct effect on parasite clearance in this model.