After Treg-cell removal, a reduced production of IL-10 was observed, but IL-2 levels were unchanged. The numbers of IL-10-producing Treg cells also increased during
infection, although the in vitro neutralization of this cytokine did not modify T-cell Nutlin-3a mouse proliferation, suggesting that IL-10 does not mediate the Treg-mediated suppression. However, addition of rIL-2 in vitro fully restored T-cell proliferation from infected animals. Thus, we show that Treg cells mediate the T-cell suppression observed during acute T. gondii infection through an IL-2-dependent mechanism. Our results provide novel insights into the regulation of the immune response against T. gondii. Toxoplasma gondii is a worldwide distributed intracellular protozoan parasite that infects approximately one-third of the human population. Toxoplasmosis is usually clinically asymptomatic in healthy individuals, but it can cause severe complications in pregnant women and immunocompromised patients. In the latter, chronic infection can reactivate leading
to disseminated toxoplasmosis and/or encephalitis that are often lethal. Primary infection during pregnancy may lead to abortion, neonatal malformations or defects that appear during child development 1. Infection with T. gondii activates DCs to produce large amounts of IL-12 2, 3 which in turn activates NK cells and T lymphocytes MAPK inhibitor to produce IFN-γ 4, 5 leading to macrophage activation and parasite control 6, 7. A TH1 immune response and cooperation between CD4+ and CD8+ T cells are crucial for infection control 5, 8, 9. Downregulation of the extremely strong TH1 immune response caused by infection is mediated by IL-10, lipoxinA4 and IL-27 10–12. During acute Mannose-binding protein-associated serine protease infection with T. gondii a transient reduction in the proliferative response of T cells to mitogens or antigens is observed in humans and mice
13–17. Analysis of cells and molecules involved in the immunosuppression observed during T. gondii infection has shown that IFN-γ-dependent reactive nitrogen intermediates (RNIs) produced by macrophages and IL-10 are implicated in this process 16–21. However, neutralization of these molecules restores only partially T-cell proliferation capacity. Furthermore, it has been demonstrated that splenocytes from infected IL-10−/− and IRF-1−/− mice are also suppressed 19, 22, thus indicating that additional mediators are involved in immunosuppression. A recent report suggested that Treg cells could be involved in the suppression observed during other parasitic infection 23. Treg cells are CD4+ lymphocytes that constitutively express CD25 24, CTLA-4 25 and the Treg cell-specific transcription factor Foxp3 26, 27, which is required for the development and the suppressive capacity of these cells. Treg cells are involved in control of autoimmunity, immune response against tumors, tissue transplants and infectious agents 28, 29.