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Lethal granuloma disintegration in mycobacteria-infected TNFRp55-/- mice is dependent on T cells and IL-12
S Ehlers1, S Kutsch, E M Ehlers
1Division of Molecular Infection Biology, Research Center Borstel, Germany. sehlers@fz-borstel.de
Abstract:
Genetically susceptible, TNFRp55 gene-deficient (TNFRp55-/-) mice succumb to infection with Mycobacterium avium. Before their death, M. avium-infected TNFRp55-/- mice develop granulomatous lesions that, in contrast to granulomas in wild-type syngeneic mice, undergo acute disintegration. To determine the factors involved in these events, we depleted T cell subsets or neutralized the inflammatory cytokines IFN-gamma, IL-12, or TNF in TNFRp55-/- mice infected i.v. with M. avium. Infected TNFRp55-/- mice treated with a control mAb became moribund between days 26 and 34 postinfection, showing widespread inflammatory cell apoptosis within disintegrating granulomas. In contrast, TNFRp55-/- mice depleted of either CD4+ or CD8+ cells after granuloma initiation stayed healthy until at least day 38 postinfection and showed no signs of granuloma destruction. Neutralization of IL-12, but not of IFN-gamma or TNF, also protected M. avium-infected TNFRp55-/- mice from granuloma decomposition and from premature death. Treatment with dexamethasone or with a specific inhibitor of inducible NO synthase did not prevent granuloma dissolution or death of TNFRp55-/- mice. In conclusion, granuloma disintegration in TNFRp55-/- mice is a lethal event that is dependent on IL-12 and that is mediated by an excess of T cells.
Insights
Tumor Necrosis Factor receptor p55 (TNFRp55)-deficient mice infected with Mycobacterium avium experience lethal granuloma disintegration. This breakdown is driven by excess T cells and is dependent on Interleukin-12 (IL-12).
Area of Science:
- Immunology
- Infectious Diseases
- Genetics
Background:
- Tumor Necrosis Factor receptor p55 (TNFRp55) plays a role in immune responses.
- Mycobacterium avium infection in TNFRp55-deficient mice leads to fatal granuloma disintegration.
- Granuloma integrity is crucial for controlling intracellular pathogens.
Purpose of the Study:
- To investigate the factors contributing to granuloma disintegration in TNFRp55-deficient mice infected with Mycobacterium avium.
- To determine the role of T cell subsets and specific cytokines in this pathological process.
Main Methods:
- Genetically modified mice lacking the TNFRp55 gene (TNFRp55-/-) were infected intravenously with Mycobacterium avium.
- T cell subsets (CD4+ and CD8+) were depleted.
- Key inflammatory cytokines, including Interleukin-12 (IL-12), Interferon-gamma (IFN-γ), and Tumor Necrosis Factor (TNF), were neutralized.
- Mice were treated with dexamethasone or an inducible nitric oxide synthase inhibitor.
Main Results:
- TNFRp55-/- mice treated with control antibodies succumbed to infection with disintegrating granulomas.
- Depletion of CD4+ or CD8+ T cells prevented granuloma destruction and premature death.
- Neutralization of IL-12, but not IFN-γ or TNF, protected mice from granuloma decomposition and death.
- Dexamethasone or inducible nitric oxide synthase inhibition did not prevent granuloma dissolution.
Conclusions:
- Granuloma disintegration in TNFRp55-/- mice during Mycobacterium avium infection is a lethal event.
- This disintegration is mediated by an excess of T cells.
- The process is critically dependent on the cytokine Interleukin-12 (IL-12).