Tuberculosis, a major health problem in developing countries, has reemerged in recent years in many industrialized countries. The increased susceptibility of immunocompromised individuals to tuberculosis, and many experimental studies indicate that T cell-mediated immunity plays an important role in resistance. The lymphokine interferon gamma (IFN-gamma) is thought to be a principal mediator of macrophage activation and resistance to intracellular pathogens. Mice have been developed which fail to produce IFN-gamma (gko), because of a targeted disruption of the gene for IFN-gamma. Upon infection with Mycobacterium tuberculosis, although they develop granulomas, gko mice fail to produce reactive nitrogen intermediates and are unable to restrict the growth of the bacilli. In contrast to control mice, gko mice exhibit heightened tissue necrosis and succumb to a rapid and fatal course of tuberculosis that could be delayed, but not prevented, by treatment with exogenous recombinant IFN-gamma.

Understanding the immunological mechanisms of protection and pathogenesis in tuberculosis remains problematic. We have examined the extent to which tumor necrosis factor-alpha (TNF alpha) contributes to this disease using murine models in which the action of TNF alpha is inhibited. TNF alpha was neutralized in vivo by monoclonal antibody; in addition, a mouse strain with a disruption in the gene for the 55 kDa TNF receptor was used. The data from both models established that TNF alpha and the 55 kDa TNF receptor are essential for protection against tuberculosis in mice, and for reactive nitrogen production by macrophages early in infection. Granulomas were formed in equal numbers in control and experimental mice, but necrosis was observed only in mice deficient in TNF alpha or TNF receptor. TNF alpha and the 55 kDa TNF receptor are necessary conditions for protection against murine M. tuberculosis infection, but are not solely responsible for the tissue damage observed.

Mice with a targeted disruption in the f32-microglobulin (f32m) gene, which lack major histocompatibility complex class I molecules and consequently fail to develop functional CD8 T cells, provided a useful model for assessing the role ofclass I-restricted T cells in resistance to infection with virulent Mycobacterium tuberculosis. Ofmutant P2m-/-mice infected with virulent 106 M. tuberculosis, 70% were dead or moribund after 6 weeks, while all control mice expressing the P2m gene remained alive for >20 weeks. Granuloma formation occurred in mutant and control mice, but far greater numbers of tubercle bacilli were present in the lungs ofmutant mice than in controls, and caseating necrosis was seen only in P2m -/-lungs. In contrast, no differences were seen in the course of infection of mutant and control mice with an avirulent vaccine strain, bacille Calmette-Guirin (BCG). Immunization with BCG vaccine prolonged survival of I2m-/-mice after challenge with M. tuberculosis for 4 weeks but did not protect them from death. These data indicate that functional CD8 T cells, and possibly T cells bearing y6 antigen receptor, are a necessary component of a protective immune response to M. tuberculosis in mice.