IL-10 from CD4+CD25−Foxp3−CD127− Adaptive Regulatory T Cells Modulates Parasite Clearance and Pathology during Malaria Infection

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⁺CD25^hi (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. Much of the pathology of malaria infection is due to an excessive inflammatory response to the parasite. The regulatory cytokine IL-10 is known to control inflammation during malaria infections and thus protect against immunopathology, but, in so doing, it reduces the effectiveness of other immune mechanisms which remove the parasites. In order to try to dissociate these two effects of IL-10, to allow simultaneous control of infection and avoidance of pathology, we need a better understanding of the processes leading to IL-10 production, the timing of its production, and the cells that produce it. In this study we have found that the major source of IL-10 during malaria (Plasmodium yoelii) infection is adaptive regulatory CD4⁺ T cells. This population is distinct from natural regulatory T cells and classical effector T cells. IL-10 derived from these adaptive CD4⁺ T cells prevents hepatic immunopathology but also suppresses the effector T cell response, preventing parasite clearance. Further work is now required to determine how these two key cell types (anti-parasitic effector T cells and IL-10-producing regulatory T cells) are induced, so that vaccines can be designed that will induce optimal numbers of each cell type at appropriate stages of the infection.