Regulatory T Cells Enhance Susceptibility to Experimental Trypanosoma Congolense Infection Independent of Mouse Genetic Background

Abstract

Background

BALB/c mice are highly susceptible while C57BL/6 are relatively resistant to experimental Trypanosoma congolense infection. Although regulatory T cells (Tregs) have been shown to regulate the pathogenesis of experimental T. congolense infection, their exact role remains controversial. We wished to determine whether Tregs contribute to distinct phenotypic outcomes in BALB/c and C57BL/6 mice and if so how they operate with respect to control of parasitemia and production of disease-exacerbating proinflammatory cytokines.

Methodology/Findings

BALB/c and C57BL/6 mice were infected intraperitoneally (i.p) with 10 ³ T. congolense clone TC13 and both the kinetics of Tregs expansion and intracellular cytokine profiles in the spleens and livers were monitored directly ex vivo by flow cytometry. In some experiments, mice were injected with anti-CD25 mAb prior or post T. congolense infection or adoptively (by intravenous route) given highly enriched naïve CD25 ⁺ T lymphocytes prior to T. congolense infection and the inflammatory cytokine/chemokine levels and survival were monitored. In contrast to a transient and non significant increase in the percentages and absolute numbers of CD4 ⁺CD25 ⁺Foxp3 ⁺ T cells (Tregs) in C57BL/6 mouse spleens and livers, a significant increase in the percentage and absolute numbers of Tregs was observed in spleens of infected BALB/c mice. Ablation or increasing the number of CD25 ⁺ cells in the relatively resistant C57BL/6 mice by anti-CD25 mAb treatment or by adoptive transfer of CD25 ⁺ T cells, respectively, ameliorates or exacerbates parasitemia and production of proinflammatory cytokines.

Conclusion

Collectively, our results show that regulatory T cells contribute to susceptibility in experimental murine trypanosomiasis in both the highly susceptible BALB/c and relatively resistant C57BL/6 mice.

Author Summary

BALB/c mice are highly susceptible while C57BL/6 is relatively resistant to experimental Trypanosoma congolense infection. Acute death observed in infected BALB/c mice is usually associated with the excessive production of pro-inflammatory cytokines. Regulatory T cells (Tregs) have been shown to play a significant role in the pathogenesis of many diseases including those caused by parasites. However, the role of Tregs in the pathogenesis of T. congolense infection remains unclear. We were interested in addressing the following questions: Do Tregs contribute to the distinct phenotypic outcomes observed in T. congolense-infected BALB/c and C57BL/6 mice? If so, where and how do they operate with respect to parasitemia and cytokine response? By selectively altering the numbers of these cells either by targeted depletion with monoclonal antibody or adoptive transfer of highly enriched naïve CD25 ⁺ cells prior to infection, we show that Tregs impairs efficient parasite control and impacts on production of disease-exacerbating proinflammatory cytokines. Collectively, our findings suggest that Tregs contribute to enhanced susceptibility to experimental T. congolense infection in mice.