IL-10 from CD 4 + CD 25 2 Foxp 3 2 CD 127 2 Adaptive Regulatory T Cells Modulates Parasite Clearance and Pathology during Malaria Infection

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-b 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 CD4CD25 (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-7Ra, that modulates the inflammatory response to malaria. Citation: Couper KN, Blount DG, Wilson MS, Hafalla JC, Belkaid Y, et al. (2008) IL-10 from CD4CD25Foxp3CD127 Adaptive Regulatory T Cells Modulates Parasite Clearance and Pathology during Malaria Infection. PLoS Pathog 4(2): e1000004. doi:10.1371/journal.ppat.1000004 Editor: James Kazura, Center for Global Health and Diseases, United States of America Received July 27, 2007; Accepted January 16, 2008; Published February 29, 2008 Copyright: 2008 Couper et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was funded by the Wellcome Trust (grant reference number 074538). J.C.H. is supported by a fellowship from the Royal Society. Competing Interests: The authors have declared that no competing interests exist. * E-mail: eleanor.riley@lshtm.ac.uk ¤ Current address: School of Pharmacy, University of Nottingham, University Park, Nottingham, United Kingdom

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