title: Hypoxia promotes Mycobacterium tuberculosis-specific up-regulation of granulysin in human T cells.
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.
authors.affiliation: Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Sebastian F
authors.initials: SF
authors.lastname: Zenk
authors.affiliation: Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Vollmer
authors.affiliation: Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Esra
authors.initials: E
authors.lastname: Schercher
authors.affiliation: Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kallert
authors.affiliation: Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kubis
authors.affiliation: Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. steffen.stenger@uniklinik-ulm.de.
authors.forename: Steffen
authors.initials: S
authors.lastname: Stenger
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D002478:Cells, Cultured; D054884:Host-Pathogen Interactions; D006801:Humans; D000860:Hypoxia; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C075005:GNLY protein, human
keywords: Granulysin; Human; Hypoxia; Infectious immunity; Tuberculosis