Interferon-gamma-responsive nonhematopoietic cells regulate the immune response to Mycobacterium tuberculosis.
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.
Desvignes
Ludovic
L
Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Ernst
Joel D
JD
D000818:Animals; D016470:Bacteremia / Q000276:immunology / Q000382:microbiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D007737:Kynurenine / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D018410:Pneumonia, Bacterial / Q000201:enzymology / Q000276:immunology; D017471:Receptors, Interferon / Q000235:genetics; D020545:Respiratory Mucosa / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000201:enzymology / Q000276:immunology*; D000096743:Interferon gamma Receptor
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D020381:Interleukin-17; D053759:Interleukin-23; D007737:Kynurenine; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor