Abstract
The outcome of malaria infection is determined, in part, by the balance of pro-inflammatory and regulatory immune responses. Failure to develop an effective pro-inflammatory response can lead to unrestricted parasite replication, whilst failure to regulate this response leads to the development of severe immunopathology. IL-10 and TGF-β are known to be important components of the regulatory response, but the cellular source of these cytokines is still unknown. Here we have examined the role of natural and adaptive regulatory T cells in the control of malaria infection and find that classical CD4+CD25hi (and Foxp3+) regulatory T cells do not significantly influence the outcome of infections with the lethal (17XL) strain of Plasmodium yoelii (PyL). In contrast, we find that adaptive IL-10-producing, CD4+ T cells (which are CD25−, Foxp3−, and CD127− and do not produce Th1, Th2, or Th17 associated cytokines) that are generated during both PyL and non-lethal P. yoelii 17X (PyNL) infections are able to down-regulate pro-inflammatory responses and impede parasite clearance. In summary, we have identified a population of induced Foxp3− regulatory (Tr1) T cells, characterised by production of IL-10 and down regulation of IL-7Rα, that modulates the inflammatory response to malaria.
Highlights
The erythrocytic stage of malaria infection is characterised by the development of strong pro-inflammatory immune responses which, required to control parasite replication and promote clearance of infected erythrocytes, must be tightly regulated to prevent the immune-mediated pathology which is integral to the development of the severe complications of infection in humans and in a number of well-characterised animal models [1,2,3]
The regulatory cytokine IL-10 is known to control inflammation during malaria infections and protect against immunopathology, but, in so doing, it reduces the effectiveness of other immune mechanisms which remove the parasites
In this study we have found that the major source of IL-10 during malaria (Plasmodium yoelii) infection is adaptive regulatory CD4+ T cells
Summary
The erythrocytic stage of malaria infection is characterised by the development of strong pro-inflammatory immune responses which, required to control parasite replication and promote clearance of infected erythrocytes, must be tightly regulated to prevent the immune-mediated pathology which is integral to the development of the severe complications of infection in humans and in a number of well-characterised animal models [1,2,3]. Mice infected with the non-lethal variant (P. yoelii 17X; PyNL) produce no or only low levels of TGF-b and IL-10 during early acute infection and eventually control their parasitaemia [5]. Splenocytes from susceptible BALB/c mice, but not resistant DBA/2 mice, infected with PyNL produce IL-10 and TGF-beta during the early acute stage of infection, which is associated with an increase in the proportion of splenic CD25+ CD4 T cells [12]. Taken together, these studies demonstrate a causal role for immunoregulatory cytokines in suppressing parasite clearance mechanisms
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