The Journal of Experimental Medicine
Cytokines Montreal 2008
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Published 17 December 2001. doi:10.1084/jem.194.12.1847
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© Rockefeller University Press, 0022-1007/2001/12/1847/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 12, December 17, 2001 1847-1859

Original Article

 {alpha}ß T Cell Receptor-positive Cells and Interferon-{gamma}, but not Inducible Nitric Oxide Synthase, Are Critical for Granuloma Necrosis in a Mouse Model of Mycobacteria-induced Pulmonary Immunopathology

Stefan Ehlers1, Jochen Benini1, Heinz-Dieter Held2, Christiane Roeck1, Gottfried Alber3 and Stefan Uhlig2

1 Divisions of Molecular Infection Biology, Research Center Borstel, Center for Medicine and Biosciences, D-23845 Borstel, Germany
2 Pulmonary Pharmacology, Research Center Borstel, Center for Medicine and Biosciences, D-23845 Borstel, Germany
3 Institute of Immunology, College of Veterinary Medicine, D-04103 Leipzig, Germany

Address correspondence to Stefan Ehlers, Division of Molecular Infection Biology/Research Center Borstel, Center for Medicine and Biosciences, Parkallee 22, D-23845 Borstel, Germany. Phone: 49-4537-188481; Fax: 49-4537-188686; E-mail: sehlers{at}fz-borstel.de

The immunological basis of tuberculin-induced necrosis, known for more than a century as "Koch's phenomenon," remains poorly understood. Aerosol infection in mice with the highly virulent Mycobacterium avium strain TMC724 causes progressive pulmonary pathology strongly resembling caseating necrosis in human patients with tuberculosis. To identify the cellular and molecular mediators causing this pathology, we infected C57BL/6 mice and mice selectively deficient in recombinase activating gene (RAG)-1, {alpha}ß T cell receptor (TCR), {gamma}{delta} TCR, CD4, CD8, ß2-microglobulin, interferon (IFN)-{gamma}, interleukin (IL)-10, IL-12p35, IL-12p35/p40, or iNOS with M. avium by aerosol and compared bacterial multiplication, histopathology, and respiratory physiology in these mice. The bacterial load in the lung was similarly high in all mouse groups. Pulmonary compliance, as a surrogate marker for granulomatous infiltrations in the lung, deteriorated to a similar extent in all groups of mice, except in {alpha}ß TCR-knockout (KO) and IL-12–KO mice in which compliance was higher, and in IFN-{gamma} and inducible nitric oxide synthase–KO mice in which compliance was reduced faster. Progressive caseation of pulmonary granulomas never occurred in {alpha}ß TCR-KO, IL-12–KO, and IFN-{gamma}–KO mice and was reduced in CD4-KO mice. In summary, {alpha}ß TCR+ cells and IFN-{gamma} are essential for the development of mycobacteria-induced pulmonary caseous necrosis. In contrast, high mycobacterial load and extensive granulomatous infiltration per se are not sufficient to cause caseation, nor is granuloma necrosis linked to the induction of nitric oxide.

Key Words: tuberculosis • granuloma • necrosis • Koch's phenomenon • immunopathology


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