A role for natural regulatory T cells in the pathogenesis of experimental cerebral malaria.
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.
Amante
Fiona H
FH
Queensland Institute of Medical Research, Herston, QLD 4006, Australia.
Stanley
Amanda C
AC
Randall
Louise M
LM
Zhou
Yonghong
Y
Haque
Ashraful
A
McSweeney
Karli
K
Waters
Andrew P
AP
Janse
Chris J
CJ
Good
Michael F
MF
Hill
Geoff R
GR
Engwerda
Christian R
CR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000469:parasitology / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016779:Malaria, Cerebral / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018512:Parasitemia / Q000150:complications / Q000517:prevention & control; D010962:Plasmodium berghei / Q000254:growth & development; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D013997:Time Factors
D000911:Antibodies, Monoclonal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D007371:Interferon-gamma; D008156:Luciferases