Journal
NATURE MEDICINE
Volume 23, Issue 10, Pages 1220-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4395
Keywords
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Funding
- National Institute of Allergy and Infectious Disease of the National Institutes of Health (NIAID/NIH) [AI42767, AI85515, AI95178, AI100527]
- NIAID/NIH [AI125446, AI127481]
- National Institute of General Medical Science of the NIH [GM103447]
- Division of Intramural Research, NIAID/NIH
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Malaria, caused by the protozoan Plasmodium, is a devastating mosquito-borne disease with the potential to affect nearly half the world's population(1). Despite mounting substantial T and B cell responses, humans fail to efficiently control blood-stage malaria or develop sterilizing immunity to reinfections(2). Although forkhead box P3 (FOXP3)(+)CD4(+) regulatory T (T-reg) cells form a part of these responses(3-5), their influence remains disputed and their mode of action is unknown. Here we show that T-reg cells expand in both humans and mice in blood-stage malaria and interfere with conventional T helper cell responses and follicular T helper (T-FH)-B cell interactions in germinal centers. Mechanistically, T-reg cells function in a critical temporal window to impede protective immunity through cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Targeting T-reg cells or CTLA-4 in this precise window accelerated parasite clearance and generated species-transcending immunity to blood-stage malaria in mice. Our study uncovers a critical mechanism of immunosuppression associated with blood-stage malaria that delays parasite clearance and prevents development of potent adaptive immunity to reinfection. These data also reveal a temporally discrete and potentially therapeutically amenable functional role for T-reg cells and CTLA-4 in limiting antimalarial immunity.
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