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

PLoS Pathogens

Nicholas M. Anstey¹  Gabriela Minigo²  Ervi Salwati³  Kim A. Piera³  Tonia Woodberry³  Christian R. Engwerda³  Ric N. Price⁴  Emiliana Tjitra⁵  Enny Kenangalem⁵  Magdalena Plebanski⁶ 

[1] Centre for Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Churchill Hospital, Oxford, United Kingdom;Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Australia;International Health Division, Menzies School of Health Research (MSHR) and Charles Darwin University, Darwin, Australia;NIHRD-MSHR Collaborative Research Program and District Health Authority, Timika, Papua, Indonesia;National Institute of Health Research and Development (NIHRD), Ministry of Health, Jakarta, Indonesia;Queensland Institute of Medical Research, Brisbane, Australia

关键词: Regulatory T cells;    Malaria;    Malarial parasites;    T cells;    Parasitic diseases;    Plasmodium;    Parasite replication;    Cytokines;   

DOI  :  10.1371/journal.ppat.1000402

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY