Networked T cell death following macrophage infection by Mycobacterium tuberculosis

PLoS One. 2012;7(6):e38488. doi: 10.1371/journal.pone.0038488. Epub 2012 Jun 4.

Abstract

Background: Depletion of T cells following infection by Mycobacterium tuberculosis (Mtb) impairs disease resolution, and interferes with clinical test performance that relies on cell-mediated immunity. A number of mechanisms contribute to this T cell suppression, such as activation-induced death and trafficking of T cells out of the peripheral circulation and into the diseased lungs. The extent to which Mtb infection of human macrophages affects T cell viability however, is not well characterised.

Methodology/principal findings: We found that lymphopenia (<1.5 × 10(9) cells/l) was prevalent among culture-positive tuberculosis patients, and lymphocyte counts significantly improved post-therapy. We previously reported that Mtb-infected human macrophages resulted in death of infected and uninfected bystander macrophages. In the current study, we sought to examine the influence of infected human alveolar macrophages on T cells. We infected primary human alveolar macrophages (the primary host cell for Mtb) or PMA-differentiated THP-1 cells with Mtb H37Ra, then prepared cell-free supernatants. The supernatants of Mtb-infected macrophages caused dose-dependent, caspase-dependent, T cell apoptosis. This toxic effect of infected macrophage secreted factors did not require TNF-α or Fas. The supernatant cytotoxic signal(s) were heat-labile and greater than 50 kDa in molecular size. Although ESAT-6 was toxic to T cells, other Mtb-secreted factors tested did not influence T cell viability; nor did macrophage-free Mtb bacilli or broth from Mtb cultures. Furthermore, supernatants from Mycobacterium bovis Bacille de Calmette et Guerin (BCG)- infected macrophages also elicited T cell death suggesting that ESAT-6 itself, although cytotoxic, was not the principal mediator of T cell death in our system.

Conclusions: Mtb-Infected macrophages secrete heat-labile factors that are toxic to T cells, and may contribute to the immunosuppression seen in tuberculosis as well as interfere with microbial eradication in the granuloma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Bacterial / immunology
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Humans
  • Lymphocyte Count
  • Lymphopenia / complications
  • Lymphopenia / epidemiology
  • Lymphopenia / immunology
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / microbiology*
  • Macrophages, Alveolar / pathology*
  • Molecular Weight
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / immunology*
  • Prevalence
  • Signal Transduction* / drug effects
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Tuberculosis / complications
  • Tuberculosis / epidemiology
  • Tuberculosis / immunology*
  • Tuberculosis / microbiology*
  • Tumor Necrosis Factor-alpha / pharmacology
  • fas Receptor / metabolism

Substances

  • Antigens, Bacterial
  • FAS protein, human
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Caspases