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Regulation of hierarchical clustering and activation of innate immune cells by dendritic cells.

ABSTRACT: An early granulomatous response, characterized by collections of white blood cells at foci surrounding pathogens, occurs after infection by many intracellular organisms, including Listeria, but how these clusters become organized and for what purpose remain poorly understood. Here, we showed that dendritic cell (DC) activation by Listeria nucleated rapid clustering of innate cells, including granulocytes, natural killer (NK) cells, and monocytes, to sites of bacteria propagation where interleukin-12 was expressed in the spleen. Clustered NK cells expressed interferon-gamma (IFN-gamma), which was necessary for the activation and maturation of colocalized monocytes to tumor necrosis factor- and inducible nitric oxide synthase-producing DCs (TipDCs). NK cell clustering was necessary for IFN-gamma production and required pertussis-toxin-sensitive recruitment, in part mediated by the chemokine receptor CCR5, and MyD88 adaptor-mediated signaling. Thus, spatial organization of the immune response by DCs between 6 and 24 hr ensures functional activation of innate cells, which restricts pathogens before adaptive immunity is fully activated.

SUBMITTER: Kang SJ

PROVIDER: S-EPMC2858430 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Regulation of hierarchical clustering and activation of innate immune cells by dendritic cells.

Kang Suk-Jo SJ Liang Hong-Erh HE Reizis Boris B Locksley Richard M RM

Immunity 20081101 5

An early granulomatous response, characterized by collections of white blood cells at foci surrounding pathogens, occurs after infection by many intracellular organisms, including Listeria, but how these clusters become organized and for what purpose remain poorly understood. Here, we showed that dendritic cell (DC) activation by Listeria nucleated rapid clustering of innate cells, including granulocytes, natural killer (NK) cells, and monocytes, to sites of bacteria propagation where interleuki ...[more]

PMID: 19006696

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Project description:Pathogenic hantaviruses are maintained world-wide within wild, asymptomatic rodent reservoir hosts, with increasingly frequent human spillover infections resulting in severe hemorrhagic fever or cardio-pulmonary disease. With no approved therapeutics or vaccines, research has, until recently, focused on understanding the drivers of immune-mediated pathogenesis. An emerging body of work is now investigating the mechanisms that allow for asymptomatic, persistent infections of mammalian reservoir hosts with highly pathogenic RNA viruses. Despite limited experimental data, several hypotheses have arisen to explain limited or absent disease pathology in reservoir hosts. In this study, we directly tested two leading hypotheses: 1) that reservoir host cells induce a generally muted response to viral insults, and 2) that these viruses employ host-specific mechanisms of innate antiviral antagonism to limit immune activation in reservoir cells. We demonstrate that, in contrast to human endothelial cells which mount a robust antiviral and inflammatory response to pathogenic hantaviruses, primary Norway rat endothelial cells do not induce antiviral gene expression in response to infection with their endemic hantavirus, Seoul orthohantavirus (SEOV). Reservoir rat cells do, however, induce strong innate immune responses to exogenous stimulatory RNAs, type I interferon, and infection with Hantaan virus, a closely related hantavirus for which the rat is not a natural reservoir. We also find that SEOV-infected rat endothelial cells remain competent for immune activation induced by exogenous stimuli or subsequent viral infection. Importantly, these findings support an alternative model for asymptomatic persistence within hantavirus reservoir hosts: that efficient viral replication within reservoir host cells may prevent the exposure of critical motifs for cellular antiviral recognition and thus limits immune activation that would otherwise result in viral clearance and/or immune-mediated disease. Defining the mechanisms that allow for infection tolerance and persistence within reservoir hosts will reveal novel strategies for viral countermeasures against these highly pathogenic zoonotic threats.

Dataset Information

Regulation of hierarchical clustering and activation of innate immune cells by dendritic cells.

Publications

Regulation of hierarchical clustering and activation of innate immune cells by dendritic cells.

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