CD40 ligand and interferon-[gamma] induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes

• Published in: Immunology 2013-05, Vol.139 (1), p.121
• Main Authors: Klug-Micu, Georgiana M, Stenger, Steffen, Sommer, Andrea, Liu, Philip T, Krutzik, Stephan R, Modlin, Robert L, Fabri, Mario
• Format: Article
• Language: English
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12062

Summary 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-[gamma] (IFN-[gamma]). Given that IFN-[gamma] 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-[gamma], 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-[gamma] 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-[gamma] results in an antimicrobial activity against intracellular M. tuberculosis. Our data suggest that at least two parallel T-cell-mediated mechanisms, CD40L and IFN-[gamma], activate the vitamin D-dependent antimicrobial pathway and trigger antimicrobial activity against intracellular M. tuberculosis, thereby contributing to human host defence against intracellular infection. [PUBLICATION ABSTRACT]