Published online before print June 28, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.061033

Accepted for publication April 24, 2007.

Article

A Role for Natural Regulatory T Cells in the Pathogenesis of Experimental Cerebral Malaria

Fiona H. Amante^*, Amanda C. Stanley^*, Louise M. Randall^*, Yonghong Zhou^*, Ashraful Haque^*, Karli McSweeney^*, Andrew P. Waters, Chris J. Janse, Michael F. Good^*, Geoff R. Hill^*, and Christian R. Engwerda^*@

From the Queensland Institute of Medical Research,* Herston, Queensland, Australia; the School of Population Health, University of Queensland, Herston, Queensland, Australia; and the Department of Parasitology, Leiden University Medical Centre, Leiden, The Netherlands

^@ To whom correspondence should be addressed. E-mail: christian.engwerda{at}qimr.edu.au.

	Abstract

Cerebral malaria (CM) is a serious complication of Plasmodium falciparum infection that is responsible for a significant number of deaths in children and nonimmune adults. A failure to control blood parasitemia and subsequent sequestration of parasites to brain microvasculature are thought to be key events in many CM cases. Here, we show for the first time, to our knowledge, that CD4⁺CD25⁺Foxp3⁺ natural regulatory T (Treg) cells contribute to pathogenesis by modulating immune responses in P. berghei ANKA (PbA)-infected mice. Depletion of Treg cells with anti-CD25 monoclonal antibody protected mice from experimental CM. The accumulation of parasites in the vasculature and brain was reduced in these animals, resulting in significantly lower parasite burdens compared with control animals. Mice lacking Treg cells had increased numbers of activated CD4⁺ and CD8⁺ T cells in the spleen and lymph nodes, but CD8⁺ T-cell recruitment to the brain was selectively reduced in these mice. Importantly, a non-Treg-cell source of interleukin-10 was critical in preventing experimental CM. Finally, we show that therapeutic administration of anti-CD25 monoclonal antibody, even when blood parasitemia is established, can prevent disease, confirming a critical and paradoxical role for Treg cells in experimental CM pathogenesis.

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