Interferon-γ-Responsive Nonhematopoietic Cells Regulate the Immune Response to Mycobacterium tuberculosis

SummaryImmunity to Mycobacterium tuberculosis in humans and in mice requires interferon gamma (IFN-γ). Whereas IFN-γ has been studied extensively for its effects on macrophages in tuberculosis, we determined that protective immunity to tuberculosis also requires IFN-γ-responsive nonhematopoietic cells. Bone marrow chimeric mice with IFN-γ-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-γ responsiveness in nonhematopoietic cells in regulation of immunity to M. tuberculosis and illustrate the role of IDO in the inhibition of Th17 cell responses.