RESUMO
Listeria monocytogenes infection induces a strong inflammatory response characterized by the production of IL-12 and IFN-gamma and protective immunity against this pathogen is dependent on CD8+ T cells (CTL). Recent studies have suggested that these inflammatory cytokines affect the rate of memory CD8+ T cell generation as well as the number of short-lived effector cells generated. The role of the closely related cytokine, IL-23, in this response has not been examined. We hypothesized that IL-12 and IL-23 produced by dendritic cells collectively enhance the generation and function of memory cells. To test this hypothesis, we employed a DC vaccination approach. Mice lacking IL-12 and IL-23 were vaccinated with wild-type (WT), IL-12(-/-), or IL-12/23(-/-) DC and protection to Lm was monitored. Mice vaccinated with WT and IL-12(-/-) DC were resistant to lethal challenge with Lm. Surprisingly, mice vaccinated with IL-12/23(-/-) DC exhibited significantly reduced protection when challenged. Protection correlated with the relative size of the memory pools generated. In summary, these data indicate that IL-23 can partially compensate for the lack of IL-12 in the generation protective immunity against Lm.
Assuntos
Células Dendríticas/imunologia , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Listeria monocytogenes/imunologia , Listeriose/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Células Cultivadas , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Imunidade Celular/genética , Memória Imunológica/genética , Imunoterapia Ativa , Interleucina-12/genética , Interleucina-23/genética , Listeria monocytogenes/patogenicidade , Listeriose/genética , Listeriose/metabolismo , Listeriose/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos TransgênicosRESUMO
Dendritic cells (DC) are required for the immune response against Listeria monocytogenes and are permissive for infection in vivo and in vitro. However, it is unclear if DC provide a desirable intracellular niche for bacterial growth. To address this issue, we have compared the behaviour of L. monocytogenes in murine bone marrow-derived DC and macrophages (BMM). Similar to BMM, bacteria escaped to the cytosol in DC, replicated, and spread to adjacent cells. However, DC infection was less robust in terms of intracellular doubling time and total increase in bacterial numbers. Immunofluorescence analysis using a strain of L. monocytogenes that expresses green fluorescent protein upon bacterial entry into the cytosol suggested that a subpopulation of DC restricted bacteria to vacuoles, a finding that was confirmed by electron microscopy. In unstimulated DC cultures, L. monocytogenes replicated preferentially in phenotypically immature cells. Furthermore, DC that were induced to mature prior to infection were poor hosts for bacterial growth. We conclude that DC provide a suboptimal niche for L. monocytogenes growth, and this is at least in part a function of the DC maturation state. Therefore, the generation of an effective T cell response may be a net effect of both productive and non-productive infection of DC.
