Natural regulatory T cells in malaria: host or parasite allies?

Abstract

Plasmodium falciparum malaria causes 500 million clinical cases with approximately one million deaths each year. After many years of exposure, individuals living in endemic areas develop a form of clinical immunity to disease known as premunition, which is characterised by low parasite burdens rather than sterilising immunity. The reason why malaria parasites persist under a state of premunition is unknown but it has been suggested that suppression of protective immunity might be a mechanism leading to parasite persistence. Although acquired immunity limits the clinical impact of infection and provides protection against parasite replication, experimental evidence indicates that cell-mediated immune responses also result in detrimental inflammation and contribute to the aetiology of severe disease. Thus, an appropriate regulatory balance between protective immune responses and immune-mediated pathology is required for a favourable outcome of infection. As natural regulatory T (T(reg)) cells are identified as an immunosuppressive lineage able to modulate the magnitude of effector responses, several studies have investigated whether this cell population plays a role in balancing protective immunity and pathogenesis during malaria. The main findings to date are summarised in this review and the implication for the induction of pathogenesis and immunity to malaria is discussed.

Figure 1. T_reg cells in malaria: Lessons learnt from experimental rodent models.

(A) In murine models characterised by high pro-inflammatory responses to infection, T_reg cell depletion may result in a strong and rapid cellular immune response, which could rapidly control parasitemia, in turn reducing parasite-mediated pathology. MØ, macrophage. (B) In an infection setting resulting in poor inflammatory responses to malaria, a lack of T_reg cells may improve the induction of such responses but at levels that are not sufficient to control parasite burden or induce immunopathology. (C) In re-infection models, T_H1 responses generated in the absence of T_reg cells during primary exposure appear to be robust enough to facilitate control of parasitemia in a secondary challenge at the expense of increased immune-mediated severe disease induction.