A Gamma Interferon Independent Mechanism of CD4 T Cell Mediated Control of M. Tuberculosis Infection in Vivo

PLoS Pathog. 2011 May;7(5):e1002052. doi: 10.1371/journal.ppat.1002052. Epub 2011 May 19.

Abstract

CD4 T cell deficiency or defective IFNγ signaling render humans and mice highly susceptible to Mycobacterium tuberculosis (Mtb) infection. The prevailing model is that Th1 CD4 T cells produce IFNγ to activate bactericidal effector mechanisms of infected macrophages. Here we test this model by directly interrogating the effector functions of Th1 CD4 T cells required to control Mtb in vivo. While Th1 CD4 T cells specific for the Mtb antigen ESAT-6 restrict in vivo Mtb growth, this inhibition is independent of IFNγ or TNF and does not require the perforin or FAS effector pathways. Adoptive transfer of Th17 CD4 T cells specific for ESAT-6 partially inhibited Mtb growth while Th2 CD4 T cells were largely ineffective. These results imply a previously unrecognized IFNγ/TNF independent pathway that efficiently controls Mtb and suggest that optimization of this alternative effector function may provide new therapeutic avenues to combat Mtb through vaccination.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, Bacterial / immunology*
  • Bacterial Proteins / immunology*
  • Fas Ligand Protein / metabolism
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium tuberculosis / immunology*
  • Mycobacterium tuberculosis / pathogenicity
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase Type II / biosynthesis
  • Perforin / metabolism
  • Th1 Cells / immunology*
  • Tuberculosis / immunology*
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • ESAT-6 protein, Mycobacterium tuberculosis
  • Fas Ligand Protein
  • Tumor Necrosis Factor-alpha
  • Perforin
  • Nitric Oxide
  • Interferon-gamma
  • Nitric Oxide Synthase Type II