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Eicosanoid pathways regulate adaptive immunity to Mycobacterium tuberculosis

Nature Immunology volume 11, pages 751–758 (2010)Cite this article

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Abstract

The fate of infected macrophages has an essential role in protection against Mycobacterium tuberculosis by regulating innate and adaptive immunity. M. tuberculosis exploits cell necrosis to exit from macrophages and spread. In contrast, apoptosis, which is characterized by an intact plasma membrane, is an innate mechanism that results in lower bacterial viability. Virulent M. tuberculosis inhibits apoptosis and promotes necrotic cell death by inhibiting production of prostaglandin E2. Here we show that by activating the 5-lipoxygenase pathway, M. tuberculosis not only inhibited apoptosis but also prevented cross-presentation of its antigens by dendritic cells, which impeded the initiation of T cell immunity. Our results explain why T cell priming in response to M. tuberculosis is delayed and emphasize the importance of early immunity.

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Figure 1: Inhibition by 5-lipoxygenase of the early initiation of an immune response after M. tuberculosis infection.
Figure 2: Transfer of M. tuberculosis–infected Alox5−/− macrophages into wild-type mice recapitulates the phenotype of intact Alox5−/− mice.
Figure 3: Transfer of infected Alox5−/− alveolar macrophages generates pulmonary and systemic CD4+ and CD8+ T cell responses.
Figure 4: CD8+ T cell activation induced by M. tuberculosis–infected Alox5−/− macrophages requires cross-presentation by CD11c+ DCs.
Figure 5: Caspase-dependent apoptosis of M. tuberculosis-infected Alox5−/− macrophages is required for the early initiation of T cell immunity.

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Acknowledgements

We thank B. Koller (University of North Carolina) for Alox5−/− and Ptges−/− mice. Supported by the US National Institutes of Health (AI 067731 to S.M.B. and AI072143 to H.G.R.), the Fonds de la Recherche en Santé du Québec (M.D.) and Fundação para a Ciência e Tecnologia of Portugal (C.N.-A.).

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  1. Maziar Divangahi

    Present address: Present address: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Canada.,

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  1. Division of Rheumatology, Department of Medicine, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Maziar Divangahi, Danielle Desjardins, Cláudio Nunes-Alves, Heinz G Remold & Samuel M Behar

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Contributions

M.D., D.D., C.N.-A. and S.M.B. designed, did and analyzed experiments; and M.D., H.G.R. and S.M.B. wrote the manuscript with advice from D.D. and C.N.-A.

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Correspondence to Heinz G Remold or Samuel M Behar.

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Divangahi, M., Desjardins, D., Nunes-Alves, C. et al. Eicosanoid pathways regulate adaptive immunity to Mycobacterium tuberculosis. Nat Immunol 11, 751–758 (2010). https://doi.org/10.1038/ni.1904

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