Cytoklne and cytokine receptor gene knockout mice provide powerful experimental systems to characterize the functions of these molecules in resistance to infectlous dlsease. Such mice may also provide unique models of immune deficiency to learn whether manipulation of the Immune response can overcome the specific dysfunction. We demonstrate that resistance of IFNy gene knockout (GKO-I-) mice to the intracellular bacterium Listerla monocytogenes is severely impaired compared with wild-type mice. However, immunization of GKO-‘-mice with an attenuated L. monocytogenes strain generates antlgen-specific CD8 T cell responses that can transfer Immunity to naive hosts. Furthermore, vaccinated GKO+ mice themselves exhibit 20,000-fold Increased resistance to challenge with virulent L. monocytogenes and this resistance appears to be CD8 T cell medlated. These studies demonstrate that vaccination-induced Immunity can overcome the absence of a cytoklne that Is critical for resistance to acute infection.

Infection of mice with Listeria monocytogenes, a human bacterial pathogen associated with severe infections of immunocompromised individuals, has sewed as a model system for innate immunity and specific immunity to infectious disease (Kaufmann, 1993). L. monocytogenes is a facultative intracellular bacterium that infects macrophages and a variety of nonphagocytic cells, including hepatocytes (Cossart and Mengaud, 1989). The biology of L. monocytogenes infection has been characterized through the analysis of mutant organisms, attenuated for virulence in the mouse model, which exhibit specific defects in the pathogenesis of in vitro infection (Portnoy et al., 1992). L. monocytogenes enters the infected cell in a phagosome but escapes from this structure into the cytoplasm primarily through the actions of a secreted bacterial hemolysin, listeriolysin 0 (LLO). LLO-mutants fail to escape from the phagosome and are avirulent (Cossart et al., 1989). Once in the cytoplasm of the eukatyotic cell, L. monocytogenes replicates and initiates movement through polymerization of host-derived F-actin, a process dependent on the L. monocytogenes Act A protein (Kocks