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CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity

Nature volume 420, pages 502–507 (2002)Cite this article

Abstract

The long-term persistence of pathogens in a host that is also able to maintain strong resistance to reinfection, referred to as concomitant immunity, is a hallmark of certain infectious diseases, including tuberculosis and leishmaniasis. The ability of pathogens to establish latency in immune individuals often has severe consequences for disease reactivation1,2,3. Here we show that the persistence of Leishmania major in the skin after healing in resistant C57BL/6 mice is controlled by an endogenous population of CD4+CD25+ regulatory T cells. These cells constitute 5–10% of peripheral CD4+ T cells in naive mice and humans, and suppress several potentially pathogenic responses in vivo, particularly T-cell responses directed against self-antigens4. During infection by L. major, CD4+CD25+ T cells accumulate in the dermis, where they suppress—by both interleukin-10-dependent and interleukin-10-independent mechanisms—the ability of CD4+CD25- effector T cells to eliminate the parasite from the site. The sterilizing immunity achieved in mice with impaired IL-10 activity is followed by the loss of immunity to reinfection, indicating that the equilibrium established between effector and regulatory T cells in sites of chronic infection might reflect both parasite and host survival strategies.

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Figure 1: CD4+CD25+ T cells from chronic lesions are suppressive and secrete IL-10 in response to L. major in vitro.
Figure 2: Lesion-derived CD4+CD25+ T cells suppress L. major immunity mediated by CD4+CD25- T cells in vivo.
Figure 3: CD4+CD25+ T cells accumulating in chronic sites originate from naturally occurring CD4+CD25+ regulatory T cells.
Figure 4: IL-10 produced by CD4+CD25+ T cells is required for parasite persistence and for the maintenance of immunity to reinfection.

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Acknowledgements

We thank C. Eigsti and K. Holmes of the Flow Cytometry Unit for FACS sorting, S. Cooper for help with the mouse care, S. Hieny for providing Toxoplasma gondii tachyzoites, M. Udey for helpful discussion, and A. Sher and G. Milon for critical reading of the manuscript.

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Author notes

  1. Yasmine Belkaid

    Present address: Research Foundation, Division of Molecular Immunology, Children's Hospital, 3333 Burnet Avenue, Cincinnati, Ohio, MLC 7021 452229, USA

  2. Yasmine Belkaid, Ciriaco A. Piccirillo and Ethan M. Shevach: These authors contributed equally to this work

Authors and Affiliations

  1. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Yasmine Belkaid, Susana Mendez & David L. Sacks

  2. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Ciriaco A. Piccirillo & Ethan M. Shevach

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Correspondence to Yasmine Belkaid.

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Belkaid, Y., Piccirillo, C., Mendez, S. et al. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002). https://doi.org/10.1038/nature01152

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