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Distinguishing Differential Responses of Dendritic Cells to Listeria monocytogenes Infection

            Dendritic Cells (DCs) have long been considered the sentinels of the immune system. Upon encounter with a pathogen they mature and optimize their ability to activate T-cells, through the upregulation of costimulatory molecules and cytokine production. Intracellular pathogens such as Listeria monocytogenes (L.m.) have been shown, by our lab, to cause a robust maturation response in dendritic cells if bacteria enter the cytosol. Furthermore, the degree of up-regulation of costimulatory molecules (i.e. CD86) directly correlates with the multiplicity of infection as measured by flow cytometry. However, microscopic examination of L.m. infected dendritic cells, revealed that direct infection and maturation did not directly correlate on a per cell basis. In fact, four distinct populations were detected. Two predicted phenotypes were mature infected cells and immature uninfected cells. Additionally, two unpredicted phenotypes were mature uninfected cells and immature infected cells. This led to two main questions: First, what prevents the maturation of some infected cells? Second, what signals are required to mature uninfected cells?

            We hypothesize that because cytoplasmic localization of L.m. is necessary to induce maturation (Brzoza et al. 2004), DCs that fail to mature may contain only phagosomally localized bacteria. Consistent with this hypothesis, we have found a subset of mDCs with bacteria lacking host cell actin polymerization, a process that requires cytoplasmic invasion. Secondly, our preliminary studies further suggest that uninfected DCs can be potently induced to mature by soluble factors secreted by infected cells. Taken together, these data illustrate the many potential mechanisms through which DCs respond to bacterial infection