Interferon gamma (IFN-γ) plays a critical role in resistance to Mycobacterium tuberculosis infection. Mice lacking IFN-γ (gko mice) develop severe tuberculosis despite forming granulomas, as they fail to produce reactive nitrogen intermediates (RNI) and cannot control bacilli growth. These mice exhibit increased tissue necrosis and succumb to the infection, but treatment with exogenous IFN-γ can delay but not prevent death. IFN-γ is essential for macrophage activation and resistance to intracellular pathogens, including M. tuberculosis. Studies show that IFN-γ is produced primarily by T cells and NK cells and is crucial for immune responses against M. tuberculosis. In gko mice, the absence of IFN-γ leads to reduced NOS mRNA expression and lower RNI production, indicating that IFN-γ is necessary for RNI generation, a key microbicidal mechanism. Reconstitution of gko mice with exogenous IFN-γ improves survival and reduces bacillary load, but does not fully restore immune function. These findings suggest that IFN-γ is essential for controlling M. tuberculosis infection, and its deficiency may contribute to the increased susceptibility of immunocompromised individuals, such as those with AIDS. The results highlight the importance of IFN-γ in the immune response to M. tuberculosis and support its potential as a therapeutic agent in tuberculosis treatment.Interferon gamma (IFN-γ) plays a critical role in resistance to Mycobacterium tuberculosis infection. Mice lacking IFN-γ (gko mice) develop severe tuberculosis despite forming granulomas, as they fail to produce reactive nitrogen intermediates (RNI) and cannot control bacilli growth. These mice exhibit increased tissue necrosis and succumb to the infection, but treatment with exogenous IFN-γ can delay but not prevent death. IFN-γ is essential for macrophage activation and resistance to intracellular pathogens, including M. tuberculosis. Studies show that IFN-γ is produced primarily by T cells and NK cells and is crucial for immune responses against M. tuberculosis. In gko mice, the absence of IFN-γ leads to reduced NOS mRNA expression and lower RNI production, indicating that IFN-γ is necessary for RNI generation, a key microbicidal mechanism. Reconstitution of gko mice with exogenous IFN-γ improves survival and reduces bacillary load, but does not fully restore immune function. These findings suggest that IFN-γ is essential for controlling M. tuberculosis infection, and its deficiency may contribute to the increased susceptibility of immunocompromised individuals, such as those with AIDS. The results highlight the importance of IFN-γ in the immune response to M. tuberculosis and support its potential as a therapeutic agent in tuberculosis treatment.