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

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

Joel Ernst, M.D., Acting Director, Division of Infectious Diseases & Immunology

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

Immunity, Volume 31, Issue 6, 974-985, 18 December 2009

Ludovic Desvignes1 and Joel D. Ernst1, 2, 3

1 Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, 550 First Avenue, Smilow 901, New York, NY 10016, USA
2 Department of Pathology, New York University School of Medicine, 550 First Avenue, Smilow 901, New York, NY 10016, USA
3 Department of Microbiology, New York University School of Medicine, 550 First Avenue, Smilow 901, New York, NY 10016, USA




A recent project in the Ernst Lab began with the goal of determining how the cytokine interferon gamma (IFNγ) contributes to protective immunity in tuberculosis (TB). While much work has been done to characterize the actions of IFNγ on macrophages in TB, Ernst and colleagues set out to determine whether responses of nonhematopoietic cells to IFNγ also play a role. The initial experiments demonstrated that bone marrow chimeric mice whose hematopoietic cells expressed IFNγ receptors, but whose nonhematopoietic cells did not, succumbed to TB approximately 2 1/2 months after infection, and that the lungs of the infected chimeric mice were infiltrated with large numbers of inflammatory cells, especially neutrophils.

Investigation of the mechanism underlying the excessive inflammation revealed that the lungs of the TB-infected chimeric mice expressed excessive quantities of IL-17, as well as the cytokines that drive Th17 differentiation, including IL-6 and IL-23. Efforts to understand how IFNγ responsiveness of nonhematopoietic cells contributes to regulation of Th17 responses revealed that the IFNγ-responsive gene encoding the enzyme indoleamine-2,3-dioxygenase (IDO) was dramatically underexpressed in epithelial and endothelial cells in the lungs of TB-infected chimeric mice.

Subsequent in vitro experiments revealed that products of IDO catabolism of its substrate, tryptophan, inhibit differentiation of naive CD4+ T cells into Th17 cells, indicating that IFNγ induction of IDO expression by epithelial and endothelial cells contributes to regulation of immune responses by generating specific tryptophan catabolites (termed kynurenines) that control Th17-mediated inflammation.

The results suggest that excessive Th17 responses to M. tuberculosis antigens may drive lung tissue damage such as that which occurs in cavitary tuberculosis. They also suggest that kynurenines may be lead compounds for discovery of drugs that regulate Th17 responses in diseases such as multiple sclerosis and inflammatory bowel disease.

The studies were conducted in the Ernst Lab by Ludovic Desvignes, Ph.D., and were made possible by invaluable help from Juan Lafaille, Ph.D.




Illustration:
Photomicrograph of M. tuberculosis in macrophages and dendritic cells in a granuloma (Reprinted by permission from the Ernst Lab)


Read a related news announcement on the recent research from the Ernst Lab by the Office of Publications and Public Affairs.


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