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Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4

Nature Medicine volume 23, pages 1220–1225 (2017)Cite this article

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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.

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Figure 1: Treg cells expand and modulate T helper cell responses and immunity to malaria.
Figure 2: CTLA-4 expression is enhanced in malaria and is integral to TFH–B–TFR cell interactions in GCs.
Figure 3: CTLA-4 blockade enhances CD4+ T cell and B cell responses, GC reaction, and antibody titers after P. yoelii infection.
Figure 4: Therapeutic blockade of CTLA-4 enhances immunity to malaria.

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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.

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Authors and Affiliations

  1. 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

  2. Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Rockville, Maryland, USA

    Nyamekye Obeng-Adjei & Peter D Crompton

  3. 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

  4. Interdisciplinary Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    Noah S Butler & John T Harty

  5. Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

    John T Harty

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  1. Samarchith P Kurup
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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.

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Correspondence to John T Harty.

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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

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