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Defective CCR7 expression on dendritic cells contributes to the development of visceral leishmaniasis

Nature Immunology volume 3, pages 1185–1191 (2002)Cite this article

Abstract

Interaction between dendritic cells (DCs) and T cells is essential for the generation of cell-mediated immunity. Here we show that DCs from mice with chronic Leishmania donovani infection fail to migrate from the marginal zone to the periarteriolar region of the spleen. Stromal cells were fewer, which was associated with loss of CCL21 and CCL19 expression. The residual stromal cells and endothelium produced sufficient CCL21 to direct the migration of DCs transferred from naïve mice. However, DCs from infected mice had impaired migration both in naïve recipients and in vitro, in response to CCL21 and CCL19. Defective localization was attributable to tumor necrosis factor-α–dependent, interleukin 10–mediated inhibition of CCR7 expression. Effective immunotherapy was achieved with CCR7-expressing DCs, without the need to identify protective Leishmania antigens. Thus defective DC migration plays a major role in the pathogenesis of this disease and the immunosuppression is mediated, at least in part, through the spatial segregation of DCs and T cells.

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Figure 1: Changes in DC distribution during L. donovani infection.
Figure 2: gp38+ stromal cells, CCL21 and CCL19 expression and T zone reticular fibers during chronic infection.
Figure 3: Stromal cells and CCL21 expression in the absence of TNF-α.
Figure 4: Migration of splenic DCs from L. donovani–infected mice.
Figure 5: Chemotactic responses of DCs to CCR7 ligands.
Figure 6: CCR7 expression on DCs from infected mice.
Figure 7: Role of TNF-α and IL-10 in regulating DC migration.
Figure 8: Immunotherapy with CCR7+ DC.

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Acknowledgements

We thank staff at the LSHTM Biological Services Unit for assistance in the breeding and maintenance of mouse colonies. We also thank A. Sher and J. Aliberti for comments on this manuscript. Supported by the Wellcome Trust and the British Medical Research Council.

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  1. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK

    Manabu Ato, Simona Stäger, Christian R. Engwerda & Paul M. Kaye

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Correspondence to Paul M. Kaye.

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Ato, M., Stäger, S., Engwerda, C. et al. Defective CCR7 expression on dendritic cells contributes to the development of visceral leishmaniasis. Nat Immunol 3, 1185–1191 (2002). https://doi.org/10.1038/ni861

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