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

Cerebral malaria (CM) is a serious complication of Plasmodiumfalciparum infection that is responsible for a significant numberof deaths in children and nonimmune adults. A failure to controlblood parasitemia and subsequent sequestration of parasitesto brain microvasculature are thought to be key events in manyCM cases. Here, we show for the first time, to our knowledge,that CD4⁺CD25⁺Foxp3⁺ natural regulatory T (Treg) cells contributeto pathogenesis by modulating immune responses in P. bergheiANKA (PbA)-infected mice. Depletion of Treg cells with anti-CD25monoclonal antibody protected mice from experimental CM. Theaccumulation of parasites in the vasculature and brain was reducedin these animals, resulting in significantly lower parasiteburdens compared with control animals. Mice lacking Treg cellshad increased numbers of activated CD4⁺ and CD8⁺ T cells inthe spleen and lymph nodes, but CD8⁺ T-cell recruitment to thebrain was selectively reduced in these mice. Importantly, anon-Treg-cell source of interleukin-10 was critical in preventingexperimental CM. Finally, we show that therapeutic administrationof anti-CD25 monoclonal antibody, even when blood parasitemiais established, can prevent disease, confirming a critical andparadoxical role for Treg cells in experimental CM pathogenesis.