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.

Regulatory issues in immunity to liver and blood-stage malaria

“…The naturally chronic P. chabaudi infection generates protracted peaks and dips [32] compared to the relatively quicker, yet similar pattern seen with P. yoelii (17XNL) infection [57]. Treg cell kinetics in malaria also shows a defined peak during the course of the infection in humans [30] and mice [58]. Understanding the kinetics of relevant immune responses may help time the interventions suitably for more predictable, favorable and reproducible outcomes in an infection.…”

IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

“…However, with some infections IL10 impedes the ability of the host immune response to eliminate the pathogen, thereby contributing to chronic infection [19,20,21]. In contrast the ablation of IL10 signaling during infection increases pathogen clearance but is accompanied by an exaggerated immunopathology [21,22,23]. These effects demonstrate the dichotomy of IL10 activity during infection.…”

Preserved Dendritic Cell HLA-DR Expression and Reduced Regulatory T Cell Activation in Asymptomatic Plasmodium falciparum and P. vivax Infection

“…Continued Treg cell expansion negatively impacts immune control of the infection (42), with Treg cell activation resulting in increased suppression of T cell responses (43). In humanized mice expressing HLA-DR0401, Treg cell activation has been associated with suppression of protective anti-parasitic antibody responses (44) and failure to control parasite growth.…”