Lipopolysaccharide-Activated Dendritic Cells: “Exhausted” or Alert and Waiting?

Abdi, Kaveh; Matzinger, Polly

doi:10.4049/jimmunol.1102868

Cited by 71 publications

(73 citation statements)

References 39 publications

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“…IL-12 is secreted by dendritic cells after rigorous activation by a combination of TLR and T cell-derived signals [20,21]. However, the individual subunits of IL-12 are not made in a synchronous fashion in the body.…”

Section: The Parts Are More Than the Summentioning

confidence: 99%

Making many from few: IL-12p40 as a model for the combinatorial assembly of heterodimeric cytokines

Abdi

Singh

2015

Cytokine

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How dendritic cells (DCs) gather information from the local milieu at a site of infection or injury and communicate this to influence adaptive immunity is not well understood. We and others have reported that soon after microbial encounter, DCs secrete the p40 subunit of IL-12, by itself, in a monomeric form. Based on recent data that this p40 monomer subsequently associates with p35 released from other cells to generate functional IL-12, we proposed that p40 can function as a DC-derived probe which samples the composition of the local milieu by looking for other binding partners. In this opinion, we discuss how such a sampling function might generate an elaborate combinatorial “code” of heterodimeric cytokines, capable of conveying location-specific information to cells downstream of DC activation, including NK and T cells.

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Section: The Parts Are More Than the Summentioning

confidence: 99%

Making many from few: IL-12p40 as a model for the combinatorial assembly of heterodimeric cytokines

Abdi

Singh

2015

Cytokine

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“…The mechanism of this feedback could involve cell-intrinsic or -extrinsic suppression of inappropriate MHC class II high DCs, perhaps transduced by MHC class II molecules (219, 220). cDCs of MARCH1-deficient mice may be analogous to hypothetical “exhausted” DCs (221–223) or to endotoxin tolerant macrophages, which are unresponsive to endotoxin stimulation partly as a result of altered NF-κB activation, chromatin modifications, and upregulated expression of negative regulators of signal transduction (179, 224, 225). Alternatively, the intracellular localization of ubiquitinated MHC class II species may positively regulate TLR and CD40 signals.…”

Section: Mhc Class II Molecules and Dendritic Cell Functionsmentioning

confidence: 99%

Molecular Control of Steady-State Dendritic Cell Maturation and Immune Homeostasis

Hammer

Ma²

2013

Annu. Rev. Immunol.

137

111

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Dendritic cells (DCs) are specialized sentinels responsible for coordinating adaptive immunity. This function is dependent upon coupled sensitivity to environmental signs of inflammation and infection to cellular maturation—the programmed alteration of DC phenotype and function to enhance immune cell activation. Although DCs are thus well equipped to respond to pathogens, maturation triggers are not unique to infection. Given that immune cells are exquisitely sensitive to the biological functions of DCs, we now appreciate that multiple layers of suppression are required to restrict the environmental sensitivity, cellular maturation, and even life span of DCs to prevent aberrant immune activation during the steady state. At the same time, steady-state DCs are not quiescent but rather perform key functions that support homeostasis of numerous cell types. Here we review these functions and molecular mechanisms of suppression that control steady-state DC maturation. Corruption of these steady-state operatives has diverse immunological consequences and pinpoints DCs as potent drivers of autoimmune and inflammatory disease.

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“…However, a prior exposure to a low level of LPS induces a durable state of cell refractoriness to subsequent LPS challenge, a condition known as endotoxin tolerance 1-4 . The complex events underlying this phenomenon remain poorly understood, despite a recent resurgence of interest in this effect, which involves multiple downstream effector cells and mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Aryl hydrocarbon receptor control of a disease tolerance defence pathway

Bessede

Gargaro

Pallotta

et al. 2014

Nature

597

596

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Summary Disease tolerance is the ability of the host to reduce the impact of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (“endotoxin tolerance”). We found that a first exposure to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase 2, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR complex-associated Src kinase activity promoted IDO1 phosphorylation and signaling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in gram-negative and gram-positive infections, pointing to a role for AhR in contributing to host fitness.

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Lipopolysaccharide-Activated Dendritic Cells: “Exhausted” or Alert and Waiting?

Cited by 71 publications

References 39 publications

Making many from few: IL-12p40 as a model for the combinatorial assembly of heterodimeric cytokines

Making many from few: IL-12p40 as a model for the combinatorial assembly of heterodimeric cytokines

Molecular Control of Steady-State Dendritic Cell Maturation and Immune Homeostasis

Aryl hydrocarbon receptor control of a disease tolerance defence pathway

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