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

Ludovic Desvignes, et al. 2009. Immunity 31, 974–985

Speaker: Wei-Zhi, Wang(王緯智)                         Time: 13:10~14:00, May. 12, 2010

Commentator: Dr. Ai-Li Shiau (蕭璦莉老師)              Place: Room 601

Abstract:

Interferon gamma (IFN-g) is essential for controlling infection with Mycobacterium tuberculosis (M.tb).  It has been reported that deficiency of IFN-g or IFN-g receptors lead to serious mycobacterial infection in both human and experimental animal models.  IFN-g, which is predominantly secreted by T cells and NK cells, works as a macrophage-activating factor to activate macrophage and promote mycobacterial killing.  A previous study revealed that controlling intracellular pathogens requires IFN-g-responsive hematopoietic (mainly immune cells) and nonhematopoietic cells (such as epithelial cells, endothelial cells and fibroblasts)¹.  Much has been known regarding how IFN-g regulates hematopoietic cell to fight against mycobacterial infection, but the role of IFN-g-responsive nonhematopoietic cells are still unclear.  In order to study the role of IFN-g-responsive nonhematopoietic cells in M.tb infection, the authors used C57BL/6 wild-type (W) and Ifngr1^-/- (K) mice to make bone marrow chimeric mice.  The authors then use them to examine the role of IFN-g-responsive nonhematopoietic cells play in immune responses after M.tb infection.  W-k mice died earlier than w-w mice and the lung bacterial load in w-k mice was more than that in w-w mice.  The authors showed that more total cell and neutrophil infiltration in w-k mice. Authors went on to detected IFN-g-inducible gene expression in lung to understand the change immune response to M.tb in w-k mice in comparison with w-w mice.  Expression of indoleamine 2,3-dioxygenase (IDO, an enzyme catalyze typtophan) was significantly decreased and the IL-17A was increased in w-k mice.  Upregulation of IL-6, IL-23 and TGF-b were also detected to confirm the overexpression of Th17 response in w-k mice. The authors fined that kynurenines, the product of IDO, inhibited the secretion of IL-17 by Th17. The results were compatible with finding that underexpression of IDO coexisted with the overexpression of Th17 response in the lung. The authors provide first direct evidence that nonhematopoietic cells must responsived to IFN-g for establishing durable control of mycobacterial growth in the lung.

References:

1.      Effector Cells of Both Nonhemopoietic and Hemopoietic Origin Are Required for Interferon (IFN)-γ– and Tumor Necrosis Factor (TNF)-α–dependent Host Resistance to the Intracellular Pathogen, Toxoplasma gondii. George S. Yap, et al J. Exp. Med. 189, 1083–1092, 1999