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Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection

Nature Immunology volume 13, pages 188–195 (2012)Cite this article

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Abstract

Infection of erythrocytes with Plasmodium species induces clinical malaria. Parasite-specific CD4+ T cells correlate with lower parasite burdens and severity of human malaria and are needed to control blood-stage infection in mice. However, the characteristics of CD4+ T cells that determine protection or parasite persistence remain unknown. Here we show that infection of humans with Plasmodium falciparum resulted in higher expression of the inhibitory receptor PD-1 associated with T cell dysfunction. In vivo blockade of the PD-1 ligand PD-L1 and the inhibitory receptor LAG-3 restored CD4+ T cell function, amplified the number of follicular helper T cells and germinal-center B cells and plasmablasts, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, and proper function can be restored by inhibitory therapies to enhance parasite control.

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Figure 1: Human and rodent malaria induce specific phenotypic and functional characteristics of CD4+ T cell exhaustion.
Figure 2: Truncation of blood-stage P. yoelii infection with chloroquine reverses CD4+ T cell exhaustion.
Figure 3: Therapeutic in vivo blockade of PD-1 and LAG-3 in mice improves antiplasmodium CD4+ T cell response and accelerates parasite clearance.
Figure 4: Therapeutic blockade of T cell inhibitory receptors accelerates parasite clearance in genetically diverse backgrounds and prevents chronic Plasmodium infection.
Figure 5: Therapeutic in vivo blockade of PD-L1 and LAG-3 in mice enhances the differentiation of CD4+ TFH cells and plasmablasts during clinical malaria.
Figure 6: Enhanced germinal-center B cell reactions, class-switch recombination and secretion of functionally protective antibodies to plasmodium after therapeutic blockade of PD-L1 and LAG-3 during clinical malaria.

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Acknowledgements

We thank the residents of Kambila, Mali, for their participation; F. Lund (University of Rochester) for C57BL/6 Aicda−/− mice lacking the immunoglobulin heavy-chain μ-chain secretory domain; D.A.A. Vignali (St. Jude Children's Research Hospital) for hybridoma clone C9B7W; and S. Perlman, N. Schmidt and V. Badovinac for comments. Supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, the US National Institutes of Health (for work in Mali; and AI085515 and AI42767 for work in the J.T.H. laboratory) and the Department of Microbiology, University of Iowa (for work in the J.T.H. laboratory).

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Authors and Affiliations

  1. Department of Microbiology, University of Iowa, Iowa City, Iowa, USA

    Noah S Butler, Lecia L Pewe & John T Harty

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

    Jacqueline Moebius & Peter D Crompton

  3. Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Centre, Faculty of Medicine, Pharmacy, and Odonto-Stomatology, University of Bamako, Bamako, Mali

    Boubacar Traore & Ogobara K Doumbo

  4. Department of Pathology, University of Iowa, Iowa City, Iowa, USA

    Lorraine T Tygrett, Thomas J Waldschmidt & John T Harty

  5. Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, USA

    Thomas J Waldschmidt & John T Harty

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Contributions

N.S.B. and J.M. designed the experiments, did the work, analyzed the data and wrote the manuscript; T.J.W., P.D.C. and J.T.H. designed the experiments, analyzed the data and wrote the manuscript; B.T. and O.K.D. coordinated the field studies and study site participants; and L.L.P. and L.T.T. did the histological studies and analyzed the data.

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Correspondence to Peter D Crompton or John T Harty.

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Butler, N., Moebius, J., Pewe, L. et al. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat Immunol 13, 188–195 (2012). https://doi.org/10.1038/ni.2180

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