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Hypoxia promotes Mycobacterium tuberculosis-specific up-regulation of granulysin in human T cells

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Abstract

Oxygen tension affects local immune responses in inflammation and infection. In tuberculosis mycobacteria avoid hypoxic areas and preferentially persist and reactivate in the oxygen-rich apex of the lung. Oxygen restriction activates antimicrobial effector mechanisms in macrophages and restricts growth of intracellular Mycobacterium tuberculosis (M.Tb). The effect of oxygen restriction on T cell-mediated antimicrobial effector mechanisms is unknown. Therefore we determined the influence of hypoxia on the expression of granulysin, an antimicrobial peptide of lymphocytes. Hypoxia increased the antigen-specific up-regulation of granulysin mRNA and protein in human CD4+ and CD8+ T lymphocytes. This observation was functionally relevant, because oxygen restriction supported the growth-limiting effect of antigen-specific T cells against virulent M.Tb residing in primary human macrophages. Our results provide evidence that oxygen restriction promotes the expression of granulysin and suggest that this effect—in conjunction with additional T cell-mediated immune responses—supports protection against mycobacteria. The therapeutic modulation of oxygen availability may offer a new strategy for the host-directed therapy of infectious diseases with intracellular pathogens.

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Acknowledgments

We acknowledge the excellent technical support of Daniel Mayer and Mark Grieshober and the support of the Institute for Transfusion Medicine, University Hospital Ulm for supplying buffy coat preparations. We appreciate fruitful discussions with Prof. Robert L. Modlin, UCLA, Los Angeles. This work was funded by the European Union (TBVAC2020 consortium). S.K. was supported by a doctoral fellowship by the Land-Baden-Württemberg (“Kooperative Promotionskolleg Phamazeutische Biotechnologie der Hochschule Biberach und der Universität Ulm”) and the International Graduate School in Molecular Medicine Ulm. J.K. was supported by a fellowship of the graduate school “Experimentelle Medizin der Universität Ulm.”

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  1. Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany

    Sebastian F. Zenk, Michael Vollmer, Esra Schercher, Stephanie Kallert, Jan Kubis & Steffen Stenger

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  1. Sebastian F. Zenk
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Correspondence to Steffen Stenger.

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This article does not contain any studies with human participants or animals performed by any of the authors. Human peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation of buffy coat preparations from anonymous donors (Institute of Transfusion Medicine, Ulm University).

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Zenk, S.F., Vollmer, M., Schercher, E. et al. Hypoxia promotes Mycobacterium tuberculosis-specific up-regulation of granulysin in human T cells. Med Microbiol Immunol 205, 219–229 (2016). https://doi.org/10.1007/s00430-015-0442-x

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