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

Abstract

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+CD127lo 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+Foxp3hi 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+Foxp3hi 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+Foxp3hi Treg cells when developing effective malaria vaccines.

Strong Impact of CD4+Foxp3+ Regulatory T Cells and Limited Effect of T Cell-Derived IL-10 on Pathogen Clearance during Plasmodium yoelii Infection

“…Likewise, an increase in the number of CD4 + CD25 + Foxp3 + Tregs has been observed in the peripheral blood of humans infected with P. falciparum (7,8) or P. vivax (9), and is apparently associated with P. falciparum parasitemia (10). Similar results were obtained from murine malaria models using P. yoelii or P. berghei (11,12).…”

“…Phenotypic characterization of Tregs from malaria patients in Western Papua New Guinea demonstrated an upregulation of Foxp3 accompanied by increased suppressive function in patients with severe malaria, but not in those with uncomplicated malaria (8). The results of these studies suggest that CD4 +…”

Human Cord Blood CD4+CD25hi Regulatory T Cells Suppress Prenatally Acquired T Cell Responses toPlasmodium falciparumAntigens

“…Two recent studies in adults have shown that FOXP3 + T regs are expanded in infected versus noninfected adults as well as exposed versus nonexposed adults (73,74). Similar to these recent studies in adults, previous studies with cord blood have examined whether T regs are more likely to be obtained from mothers who have evidence of current or prior malaria.…”

“…Recent studies show that T regs can modify susceptibility to disease (77,78) and contribute to whether the host immune responses are protective or pathological in response to infection with P. falciparum parasites (73,(79)(80)(81)(82). The nature of the initial exposure to malaria Ags likely affects the potentially diverse roles assumed by T regs in malaria infection.…”

Reducing TNF Receptor 2+ Regulatory T Cells via the Combined Action of Azacitidine and the HDAC Inhibitor, Panobinostat for Clinical Benefit in Acute Myeloid Leukemia Patients

“…The role of distinct Treg subsets in AML is currently not known, however, a functionally active Treg subset should have a high bone marrow migratory capacity (16). TNF receptor-2 (TNFR2) expression has recently been demonstrated to identify highly functional Tregs in healthy donors (17,18) and in various diseases such as malaria (19), diabetes (20), and cancer (21). TNFR2…”