African Trypanosomiasis: Naturally Occurring Regulatory T Cells Favor Trypanotolerance by Limiting Pathology Associated with Sustained Type 1 Inflammation

Abstract

Tolerance to African trypanosomes requires the production of IFN-γ in the early stage of infection that triggers the development of classically activated macrophages controlling parasite growth. However, once the first peak of parasitemia has been controlled, down-regulation of the type 1 immune response has been described. In this study, we have evaluated whether regulatory T cells (Tregs) contribute to the limitation of the immune response occurring during Trypanosoma congolense infection and hereby influence the outcome of the disease in trypanotolerant C57BL/6 host. Our data show that Foxp3+ Tregs originating from the naturally occurring Treg pool expanded in the spleen and the liver of infected mice. These cells produced IL-10 and limited the production of IFN-γ by CD4+ and CD8+ effector T cells. Tregs also down-regulated classical activation of macrophages resulting in reduced TNF-α production. The Treg-mediated suppression of the type 1 inflammatory immune response did not hamper parasite clearance, but was beneficial for the host survival by limiting the tissue damages, including liver injury. Collectively, these data suggest a cardinal role for naturally occurring Tregs in the development of a trypanotolerant phenotype during African trypanosomiasis.

Regulatory T Cells Prevent Control of Experimental African Trypanosomiasis

“…Can our prediction be confirmed that a CD8 Ϫ subset of NKT cells promotes proliferation of Tregs in trypanosome infections? Are the regulatory loops between different cell types of the immune system that we are un- After completing this manuscript, we discovered a study on treatment with anti-CD25 Abs of relatively resistant C57BL/6 mice infected with T. congolense (34). The authors report findings and conclusions that differ from ours.…”

“…We had recently speculated that Tregs would, via IL-10, down-regulate the immunopathology in infected relatively resistant C57BL/6 mice (14). Guilliams et al (34) have now provided good evidence that Tregs control the immunopathology in T. congolense-infected C57BL/6 mice, with IL-10 being a major mediator. Although they also used administration of anti-CD25 Abs before infection, they did not, as we did, observe an early elimination of the parasites as an effect of the treatment.…”

“…How can we explain this discrepancy? There are three major differences in their and our experimental designs: 1) Guilliams et al (34) used a much higher dose of anti-CD25 Abs. In our hands, higher doses of anti-CD25 Abs did not lead to elimination of infection ( Figs.…”

“…1 and 2). 2) Guilliams et al (34), although they do not specifically indicate the route of infection, presumably infected the mice i.p. In the past, we also used the i.p.…”

Partial depletion of CD4+CD25+Foxp3+ T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice

“…Although initially described to regulate autoimmune responses [13,16,17], it has also been demonstrated that Treg cells can regulate the immune response against infectious agents including parasites [18e21]. In this context, in vivo depletion of CD25 þ T cells was shown to lead to an increase in IFN-g production in mice infected with Plasmodium chabaudi adami [22] and Trypanosoma congolense [23], or in animals infected with Schistosoma mansoni to an increased production of IFN-g, IL-4, IL-5 and IL-13 [24] indicating that Treg cells can control both TH1 and TH2 responses.…”