Parasite-Dependent Expansion of TNF Receptor II- Positive Regulatory T Cells with Enhanced Suppressive Activity in Adults with Severe Malaria.

Severe Plasmodium falciparum malaria is a major cause of global mortality, yet the immunological factors underlying progression to severe disease remain unclear. CD4⁺CD25⁺ regulatory T cells (Treg cells) are associated with impaired T cell control of Plasmodium spp infection. We investigated the relationship between Treg cells, parasite biomass, and P. falciparum malaria disease severity in adults living in a malaria-endemic region of Indonesia. CD4⁺CD25⁺Foxp3⁺CD127^lo Treg cells were significantly elevated in patients with uncomplicated (UM; n = 17) and severe malaria (SM; n = 16) relative to exposed asymptomatic controls (AC; n = 10). In patients with SM, Treg cell frequency correlated positively with parasitemia (r = 0.79, p = 0.0003) and total parasite biomass (r = 0.87, p < 0.001), both major determinants for the development of severe and fatal malaria, and Treg cells were significantly increased in hyperparasitemia. There was a further significant correlation between Treg cell frequency and plasma concentrations of soluble tumor necrosis factor receptor II (TNFRII) in SM. A subset of TNFRII⁺ Treg cells with high expression of Foxp3 was increased in severe relative to uncomplicated malaria. In vitro, P. falciparum-infected red blood cells dose dependently induced TNFRII⁺Foxp3^hi Treg cells in PBMC from malaria-unexposed donors which showed greater suppressive activity than TNFRII^- Treg cells. The selective enrichment of the Treg cell compartment for a maximally suppressive TNFRII⁺Foxp3^hi Treg subset in severe malaria provides a potential link between immune suppression, increased parasite biomass, and malaria disease severity. The findings caution against the induction of TNFRII⁺Foxp3^hi Treg cells when developing effective malaria vaccines. [ABSTRACT FROM AUTHOR]