CD40 ligand and interferon-γ induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes

Immunology. 2013 May;139(1):121-8. doi: 10.1111/imm.12062.

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / immunology
  • Antimicrobial Cationic Peptides / immunology
  • CD40 Ligand / agonists
  • CD40 Ligand / immunology*
  • CD40 Ligand / metabolism
  • Calcitriol / immunology
  • Cathelicidins
  • Female
  • Humans
  • Interferon-gamma / agonists
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Male
  • Monocytes / immunology*
  • Monocytes / microbiology
  • Mycobacterium tuberculosis / immunology*
  • Receptors, Calcitriol / immunology*
  • T-Lymphocytes / immunology
  • Tuberculosis / immunology*
  • beta-Defensins / immunology

Substances

  • Antimicrobial Cationic Peptides
  • DEFB4A protein, human
  • IFNG protein, human
  • Receptors, Calcitriol
  • beta-Defensins
  • CD40 Ligand
  • Interferon-gamma
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • Calcitriol
  • Cathelicidins