Strong impact of CD4 +Foxp3 + regulatory T cells and limited effect of T cell-derived IL-10 on pathogen clearance during Plasmodium yoelii infection

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 Teffector function and Treg activity, but has only a limited direct effect on parasite clearance in this model. Copyright © 2012 by The American Association of Immunologists, Inc.