αβ T Cell Receptor-positive Cells and Interferon-γ, but not Inducible Nitric Oxide Synthase, Are Critical for Granuloma Necrosis in a Mouse Model of Mycobacteria-induced Pulmonary Immunopathology
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Medientyp:
E-Artikel
Titel:
αβ T Cell Receptor-positive Cells and Interferon-γ, but not Inducible Nitric Oxide Synthase, Are Critical for Granuloma Necrosis in a Mouse Model of Mycobacteria-induced Pulmonary Immunopathology
Beschreibung:
<jats:p>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, αβ T cell receptor (TCR), γδ TCR, CD4, CD8, β2-microglobulin, interferon (IFN)-γ, 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 αβ TCR-knockout (KO) and IL-12–KO mice in which compliance was higher, and in IFN-γ and inducible nitric oxide synthase–KO mice in which compliance was reduced faster. Progressive caseation of pulmonary granulomas never occurred in αβ TCR-KO, IL-12–KO, and IFN-γ–KO mice and was reduced in CD4-KO mice. In summary, αβ TCR+ cells and IFN-γ 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.</jats:p>