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ABSTRACT Malaria, caused by the protozoan _Plasmodium_, is a devastating mosquito-borne disease with the potential to affect nearly half the world's population1. Despite mounting

substantial T and B cell responses, humans fail to efficiently control blood-stage malaria or develop sterilizing immunity to reinfections2. Although forkhead box P3 (FOXP3)+CD4+ regulatory

T (Treg) cells form a part of these responses3,4,5, their influence remains disputed and their mode of action is unknown. Here we show that Treg cells expand in both humans and mice in

blood-stage malaria and interfere with conventional T helper cell responses and follicular T helper (TFH)–B cell interactions in germinal centers. Mechanistically, Treg cells function in a

critical temporal window to impede protective immunity through cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Targeting Treg 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 Treg cells and CTLA-4 in limiting antimalarial immunity. Access through your institution Buy or subscribe This is a preview of subscription content, access via

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Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional

subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE IMPACT OF _PLASMODIUM_-DRIVEN IMMUNOREGULATORY NETWORKS ON IMMUNITY TO MALARIA Article 11

June 2024 AGE-DEPENDENT CHANGES IN CIRCULATING TFH CELLS INFLUENCE DEVELOPMENT OF FUNCTIONAL MALARIA ANTIBODIES IN CHILDREN Article Open access 18 July 2022 INTERFERON-Γ SIGNAL DRIVES

DIFFERENTIATION OF T-BETHI ATYPICAL MEMORY B CELLS INTO PLASMA CELLS FOLLOWING _PLASMODIUM VIVAX_ INFECTION Article Open access 22 March 2022 REFERENCES * World Health Organization. _World

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infection. _J. Immunol._ 185, 2382–2392 (2010). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank L. Epping and S. Hartwig for assistance; S. Varga

(University of Iowa, PC61.5 antibody), T. Waldschmidt (University of Iowa, MR-1 antibody), and D.A.A. Vignali (University of Pittsburgh, hybridoma clone C9B7W) for reagents; S. Perlman and

V. Badovinac for constructive comments; the University of Iowa Central Microscopy Research Facility; and the New York University Insectary Core Facility. Support for these studies was

provided by grants from the National Institute of Allergy and Infectious Disease of the National Institutes of Health (NIAID/NIH) (AI42767, AI85515, AI95178, and AI100527 to J.T.H.). Support

for the laboratory of N.S.B. was provided by grants from NIAID/NIH (AI125446 and AI127481) and the National Institute of General Medical Science of the NIH (GM103447). The Malian study and

the analysis of human samples were funded by the Division of Intramural Research, NIAID/NIH. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Microbiology and Immunology,

University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Samarchith P Kurup, Scott M Anthony, Noah S Butler & John T Harty * Laboratory of Immunogenetics, National Institute

of Allergy and Infectious Diseases, US National Institutes of Health, Rockville, Maryland, USA Nyamekye Obeng-Adjei & Peter D Crompton * Department of Epidemiology of Parasitic Diseases,

Malaria Research and Training Centre, International Center of Excellence in Research, University of Sciences, Technique and Technology of Bamako, Bamako, Mali Boubacar Traore & Ogobara

K Doumbo * Interdisciplinary Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Noah S Butler & John T Harty * Department of Pathology, University

of Iowa Carver College of Medicine, Iowa City, Iowa, USA John T Harty Authors * Samarchith P Kurup View author publications You can also search for this author inPubMed Google Scholar *

Nyamekye Obeng-Adjei View author publications You can also search for this author inPubMed Google Scholar * Scott M Anthony View author publications You can also search for this author

inPubMed Google Scholar * Boubacar Traore View author publications You can also search for this author inPubMed Google Scholar * Ogobara K Doumbo View author publications You can also search

for this author inPubMed Google Scholar * Noah S Butler View author publications You can also search for this author inPubMed Google Scholar * Peter D Crompton View author publications You

can also search for this author inPubMed Google Scholar * John T Harty View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS S.P.K., N.O.-A.,

S.M.A., and N.S.B. designed, performed, analyzed, and interpreted experiments. S.P.K., N.S.B., P.D.C., and J.T.H. wrote the paper. B.T., O.K.D., and P.D.C. supervised the human studies and

designed, analyzed, and interpreted experiments. J.T.H. supervised the project and designed and interpreted experiments. CORRESPONDING AUTHOR Correspondence to John T Harty. ETHICS

DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURES AND TABLE Supplementary Figures 1–14 and Supplementary

Table 1 (PDF 2025 kb) LIFE SCIENCES REPORTING SUMMARY (PDF 130 KB) CD4+ T–CELL CLUSTERS IN SPLENIC GCS OF _P. YOELLI_–INFECTED MICE. (MOV 23484 KB) TFH–B–TFR CELL CLUSTERS IN SPLENIC GCS OF

_P. YOELLI_–INFECTED MICE. (MOV 13157 KB) CLOSE APPOSITION OF B CELLS AND TFR CELLS IN GCS OF _P. YOELLI_–INFECTED MICE. (MOV 3831 KB) CTLA-4 ON THE B CELL SURFACE PROXIMAL TO A TFR CELL IN

A TFH–B–TFR CELL CLUSTER. (MOV 1481 KB) TFR CELLS TRANSIENTLY INTERACT WITH B CELLS IN THE SPLENIC GCS OF _P. YOELLI_–INFECTED MICE. (MOV 6442 KB) RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Kurup, S., Obeng-Adjei, N., Anthony, S. _et al._ Regulatory T cells impede acute and long-term immunity to blood-stage malaria through

CTLA-4. _Nat Med_ 23, 1220–1225 (2017). https://doi.org/10.1038/nm.4395 Download citation * Received: 28 April 2017 * Accepted: 05 July 2017 * Published: 11 September 2017 * Issue Date: 01

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