Interferon-gamma-responsive nonhematopoietic cells regulate the immune response to Mycobacterium tuberculosis

Immunity. 2009 Dec 18;31(6):974-85. doi: 10.1016/j.immuni.2009.10.007.

Abstract

Immunity to Mycobacterium tuberculosis in humans and in mice requires interferon gamma (IFN-gamma). Whereas IFN-gamma has been studied extensively for its effects on macrophages in tuberculosis, we determined that protective immunity to tuberculosis also requires IFN-gamma-responsive nonhematopoietic cells. Bone marrow chimeric mice with IFN-gamma-unresponsive lung epithelial and endothelial cells exhibited earlier mortality and higher bacterial burdens than control mice, underexpressed indoleamine-2,3-dioxygenase (Ido1) in lung endothelium and epithelium, and overexpressed interleukin-17 (IL-17) with massive neutrophilic inflammation in the lungs. We also found that the products of IDO catabolism of tryptophan selectively inhibit IL-17 production by Th17 cells, by inhibiting the action of IL-23. These results reveal a previously unsuspected role for IFN-gamma responsiveness in nonhematopoietic cells in regulation of immunity to M. tuberculosis and illustrate the role of IDO in the inhibition of Th17 cell responses.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bacteremia / immunology
  • Bacteremia / microbiology
  • Cells, Cultured
  • Endothelial Cells / immunology*
  • Endothelial Cells / microbiology
  • Endothelial Cells / pathology
  • Female
  • Gene Expression Profiling
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Interferon-gamma / metabolism*
  • Interleukin-17 / metabolism
  • Interleukin-23 / immunology
  • Interleukin-23 / metabolism
  • Kynurenine / immunology
  • Kynurenine / metabolism
  • Lung / immunology
  • Lung / microbiology
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycobacterium tuberculosis / immunology*
  • Neutrophil Infiltration / immunology
  • Oligonucleotide Array Sequence Analysis
  • Pneumonia, Bacterial / enzymology
  • Pneumonia, Bacterial / immunology
  • Receptors, Interferon / genetics
  • Respiratory Mucosa / immunology*
  • Respiratory Mucosa / microbiology
  • Respiratory Mucosa / pathology
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / microbiology
  • Tuberculosis, Pulmonary / enzymology
  • Tuberculosis, Pulmonary / immunology*

Substances

  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interleukin-17
  • Interleukin-23
  • Receptors, Interferon
  • interferon gamma receptor
  • Kynurenine
  • Interferon-gamma