Natural regulatory (CD4+CD25+FOXP+) T cells control the production of pro-inflammatory cytokines during Plasmodium chabaudi adami infection and do not contribute to immune evasion
Introduction
Natural Treg cells represent a population of CD4+CD45RBlow T cells constitutively expressing the α chain of the IL-2 receptor (CD25) (Schwartz, 2005) and which, in mice, comprise more than 85% of the cells expressing the Fork Head BOX P3 transcriptional factor (FOXP3) (Khattri et al., 2003, Fontenot et al., 2005). These cells play determinant roles in the preservation of self-tolerance and in the control of graft and tumor rejection and inflammation, and their abrogation leads to autoimmunity and inflammatory diseases in several experimental models (Fontenot et al., 2005, Schwartz, 2005).
In addition to their function in self-tolerance, Treg cells participate in the control of overwhelming responses to infectious agents such as viruses, bacteria and protozoan parasites (Raghavan and Holmgren, 2005, Belkaid et al., 2006, Demengeot et al., 2006, Suvas and Rouse, 2006). In malaria, Treg cells expand during infection with the Plasmodium berghei ANKA strain (Nie et al., 2007, Vigario et al., 2007) and have been shown to inhibit the development of pathogenic TH1 cells, responsible for cerebral disease in resistant BALB/c mice (Nie et al., 2007). These results contrast with the detrimental effects associated with Treg cells during P. berghei ANKA infection in susceptible C57BL/6 mice (Amante et al., 2007). In this infection model, depletion of Treg cells results in a significant increase in survival, a minor but significant reduction in blood parasitemia and an important reduction in parasite load in the brain and vasculature. A comparable delay in the onset of peak parasitemia has been reported during P. berghei NK65 infection in mice depleted of Treg cells (Long et al., 2003) and in the Plasmodium yoelii 17XL infection model, elimination of Treg cells allows BALB/c mice to control otherwise lethal infections (Hisaeda et al., 2004). Moreover, data provided by Plasmodium falciparum infections in humans correlates the expansion of natural Treg cells and the production of transforming growth factor-β (TGF-β) with higher parasite multiplication rates (Walther et al., 2005). Altogether, these observations attribute contrasting functions to natural Treg cells during Plasmodium infections.
Herein, the role of natural Treg cells in the lethality associated with Plasmodium chabaudi adami infection has been evaluated using two parasite strains with contrasting virulence, sustained by distinct parasite multiplication rates, and by the severity of inflammation and anaemia generated. Our results indicate that during P.c. adami infection, Treg cells contribute to the control of overwhelming inflammatory responses and do not impair protective immune responses.
Section snippets
Parasites, mice and infections
The P.c. adami DS (lethal) and DK (non-lethal) strains derive from two different isolates (Killick-Kendrick and Peters, 1978). Female BALB/c mice, 4–6 weeks old (Charles River), were infected with 105 parasitised red blood cells (PRBC) by the i.p. route. Parasitemia was measured daily in methanol fixed tail blood smears stained with a 10% Giemsa solution in PBS.
Cell purification
Single-cell suspensions of splenocytes from naïve and P.c. adami-infected mice (peak parasitemia) were prepared. In experiments
Pro-inflammatory cytokines responses are enhanced during lethal P.c. adami infection
In BALB/c mice and in other inbred and outbred mouse strains, inoculation of P.c. adami DS PRBCs resulted in elevated parasitemia (45–65%) and 100% mortality (Scorza et al., 2005; and unpublished results) (Fig. 1a). In contrast, similar infective doses with DK parasites resulted in moderate infection (13–20% parasitemia) that resolved 12–13 days later in BALB/c mice (Fig. 1a).
We compared the levels of TNF-α, IFN-γ and IL-10 in 72 h culture supernatants of splenic cells from BALB/c mice with DS
Discussion
In the present study, we show that the population of natural Treg cells significantly expands during lethal P.c. adami DS infections. In this malaria infection model, Treg cells contribute to down-regulation of the severe inflammatory response but fail to protect the mice from the development of lethal anaemia and death.
Regulatory T cells participate in the attenuation of overwhelming inflammatory responses during infections with protozoa and helminths (Belkaid et al., 2006). In BALB/c mice,
Acknowledgements
This work was supported by the Natural Sciences and Engineering Research Council of Canada and Le Programme d’aide à la Recherche PAFARC. M. Cambos is recipient of a FARE scholarship. The study was conducted in compliance with the regulations from the Animal Committee of the University of Quebec in Montreal (Protocol 0705-R1-508-0706).
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2014, Experimental ParasitologyCitation Excerpt :However, these studies provided limited mechanistic insight into the role of Treg cells in severe malarial disease. Numbers of studies have also showed that Treg cells may facilitate parasite clearance (Chen et al., 2009; Feng et al., 2012), limit malaria-induced immune pathology (Haque et al., 2010), enhance parasite burden (Cambos et al., 2008) and help parasite to escape host immune defense (Hisaeda et al., 2004). These observations suggest a possibility that Treg cells are able to control different types of the immune response by tailoring their suppressive function to a particular inflammatory environment.