Identification and functional analysis of non-antigenic factors of intracellular bacteria essential for the induction of cell-mediated protective immunity

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This study investigated the mechanism and the role of factors other than antigens from intracellular bacteria in the induction of T cell-mediated protective immunity. Results summarized as follows have been obtained.1. The endogenous production of γ-interferon-γ (IFN-γ) was essential for the induction of TH1-dependent immunity against intracellular bacteria. In this process, IL-12 was important among various cytokines produced by macrophages.2. One of the non-antigenic factor, LLO from Listeria monocytogenes, was highly capable of inducing cytokines. By using the liposome-encapsulated LLO in vivo, it was possible to induce the endogenous cytokines to the level comparable to that induced by immunization with viable bacteria (actual infection).3. Application of liposome-encapsulated LLO as a sort of adjuvant, a strong protective immunity could be induced after immunization of mice with LLO plus killed bacteria or LLO-negative strain, both of which are incapable of inducing protection if used alone.4. TH-1 dependent protection was ascribed to the activation of macrophages mainly induced by IFN-γ. The expression of enhanced bacterial killing in activated macrophages was due either to reactive oxygen intermediates or to reactive nitrogen intermediates, depending on the timing of activation and bacterial infection in macrophage level.5. A mechanism similar to the above appeared to be involved in the infection by Sporothrix schenkii, a possible intracellular parasitic fungus.6. In the induction of IFN-γ by LLO, both IL-12 and IL-18 were highly essential at the initial stage of macrophage stimulation by LLO. It was suggested that 15,000 kDa protein of the membrane was involved in the initial triggering.7. Among 4 domains of LLO molecule, 4th domain was indispensable for the expression of membrane damage. In contrast, domains 1 through 3 seemed to be essential for the expression of cytokine-inducing ability.