title: CD40 ligand and interferon-γ induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes.
abstract: The ability of T cells to activate antimicrobial pathways in infected macrophages is essential to host defence against many intracellular pathogens. Here, we compared the ability of two T-cell-mediated mechanisms to trigger antimicrobial responses against Mycobacterium tuberculosis in humans, CD40 activation and the release of interferon-γ (IFN-γ). Given that IFN-γ activates a vitamin D-dependent antimicrobial response, we focused on induction of the key components of this pathway. We show that activation of human monocytes via CD40 ligand (CD40L) and IFN-γ, alone, and in combination, induces the CYP27b1-hydroxylase, responsible for the conversion of 25-hydroxyvitamin D (25D) to the bioactive 1,25-dihydroxyvitamin D (1,25D), and the vitamin D receptor (VDR). The activation of the vitamin D pathway by CD40L and IFN-γ results in up-regulated expression of the antimicrobial peptides, cathelicidin and DEFB4, as well as induction of autophagy. Finally, activation of monocytes via CD40L and IFN-γ results in an antimicrobial activity against intracellular M. tuberculosis. Our data suggest that at least two parallel T-cell-mediated mechanisms, CD40L and IFN-γ, activate the vitamin D-dependent antimicrobial pathway and trigger antimicrobial activity against intracellular M. tuberculosis, thereby contributing to human host defence against intracellular infection.
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Georgiana M
authors.initials: GM
authors.lastname: Klug-Micu
authors.forename: Steffen
authors.initials: S
authors.lastname: Stenger
authors.forename: Andrea
authors.initials: A
authors.lastname: Sommer
authors.forename: Philip T
authors.initials: PT
authors.lastname: Liu
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Krutzik
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.forename: Mario
authors.initials: M
authors.lastname: Fabri
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000276:immunology; D023181:Antimicrobial Cationic Peptides / Q000276:immunology; D023201:CD40 Ligand / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D002117:Calcitriol / Q000276:immunology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D018167:Receptors, Calcitriol / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology*; D023083:beta-Defensins / Q000276:immunology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; C106641:DEFB4A protein, human; C573415:IFNG protein, human; D018167:Receptors, Calcitriol; D023083:beta-Defensins; D023201:CD40 Ligand; D007371:Interferon-gamma; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D054804:Cathelicidins