Regulatory T cells (Tregs) contribute to suppression of anti-malarial immunity by concurrent nematode infection (51.1)

Abstract

Abstract Here, we investigated the mechanisms involved in modulation of anti-malarial immunity by concurrent nematode infection. Both WT C57BL/6 (B6) and STAT-6 deficient (KO) mice co-infected with the gastrointestinal nematode Heligmosomoides polygyrus (Hp) 2 wk prior to blood-stage Plasmodium chabaudi AS (Pc) infection had significantly higher parasitemias and significantly lower serum IFN-γ levels compared to their respective controls infected with Pc alone. Hp-infected STAT-6 KO compared to WT mice produced significantly lower levels of Th2 cytokines (IL-4, IL-13) but Tregs (CD4+CD25+Foxp3− and CD4+CD25−Foxp3+) were significantly and similarly increased within 2 wk after Hp infection in both strains. Transfer of CD4+CD25+ Tregs from uninfected and Hp-infected B6 mice significantly increased malaria parasitemia in recipient mice while depletion of CD25+ cells suppressed parasitemia in Pc-infected mice but not in co-infected mice. FACS analysis revealed that anti-CD25 mAb (PC61) treatment reduced both CD4+CD25+ Tregs and CD4+Foxp3+ Tregs in Pc-infected but not in co-infected mice. Co-infection with Hp significantly enhanced Pc-induced TGF-β1 and IL-10 production. In vivo neutralization of TGF-β1 and blocking IL-10R with mAbs significantly reduced parasitemia in both Pc-infected and co-infected B6 mice; anti-IL-10R mAb treatment resulted in severe mortality. These results suggest that Tregs, and possibly immunoregulatory but not Th2 cytokines, contribute to suppression of anti-malarial immunity in nematode and malaria co-infected mice.