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

• Published in: The American journal of pathology Vol. 171; no. 2; pp. 548 - 559
• Main Authors: Amante, Fiona H, Stanley, Amanda C, Randall, Louise M, Zhou, Yonghong, Haque, Ashraful, McSweeney, Karli, Waters, Andrew P, Janse, Chris J, Good, Michael F, Hill, Geoff R, Engwerda, Christian R
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01-08-2007; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Biological and medical sciences; Brain - drug effects; Brain - parasitology; Brain - pathology; Female; Flow Cytometry; Forkhead Transcription Factors - immunology; Human protozoal diseases; Immunohistochemistry; Infectious diseases; Interferon-gamma - genetics; Interferon-gamma - metabolism; Interleukin-10 - genetics; Interleukin-10 - metabolism; Interleukin-2 Receptor alpha Subunit - immunology; Investigative techniques, diagnostic techniques (general aspects); Luciferases - genetics; Luciferases - metabolism; Lymph Nodes - drug effects; Lymph Nodes - immunology; Lymph Nodes - parasitology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Malaria; Malaria, Cerebral - etiology; Malaria, Cerebral - immunology; Malaria, Cerebral - prevention & control; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Parasitemia - complications; Parasitemia - prevention & control; Parasitic diseases; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Plasmodium berghei - growth & development; Plasmodium falciparum; Protozoal diseases; Regular; Reverse Transcriptase Polymerase Chain Reaction; Spleen - drug effects; Spleen - immunology; Spleen - parasitology; Survival Analysis; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - physiology; Time Factors; Infection; Protozoal disease; Anatomic pathology; Malaria; Pathogenesis; Pernicious attack; T-Lymphocyte; Parasitosis; Experimental study; Regulatory cell
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2007.061033

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.