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Antigen-presenting cell function in the tolerogenic liver environment

Nature Reviews Immunology volume 10, pages 753–766 (2010)Cite this article

Subjects

Key Points

  • The liver is a solid organ with unique immunoregulatory functions that are determined by the hepatic microenvironment, which is rich in regulatory soluble mediators, and by local antigen-presenting cells (APCs) with tolerogenic capabilities located within a unique anatomical microarchitecture.

  • Local hepatic APCs with tolerogenic function are myeloid and plasmacytoid dendritic cells, liver sinusoidal endothelial cells, Kupffer cells and hepatocytes. Under steady-state conditions, these cells induce T cell tolerance by numerous mechanisms, including clonal elimination, the induction of T cell anergy and the induction, recruitment or proliferation of regulatory T (TReg) cells.

  • Tolerogenic hepatic APCs characteristically resist functional maturation in response to pathogen- or danger-associated molecular patterns (PAMPs; DAMPs), which are present physiologically in portal venous blood, through the development of hyporesponsiveness towards these stimuli or through non-responsiveness due to cell-intrinsic regulatory mechanisms.

  • Microbial infection leading to the functional maturation of tolerogenic into immunogenic APCs, either by cell-autonomous mechanisms or cell–cell interactions, can result in the local induction of T cell immunity in the liver by mechanisms that still need to be defined.

  • The abundance of tolerogenic APCs within the hepatic sinusoids facilitates interaction with circulating T cells and allows the liver to function as a large immunoregulatory platform aimed at skewing hepatic, as well as extrahepatic, immune responses. The principles governing hepatic tolerance or immunity may be exploited to develop therapeutic options to mitigate autoimmunity or allograft rejection, to prolong hepatic transgene expression or to overcome tolerogenic barriers in persistent infection and cancer.

Abstract

The demands that are imposed on the liver as a result of its function as a metabolic organ that extracts nutrients and clears gut-derived microbial products from the blood are met by a unique microanatomical and immunological environment. The inherent tolerogenicity of the liver and its role in the regulation of innate and adaptive immunity are mediated by parenchymal and non-parenchymal antigen-presenting cells (APCs), cell-autonomous molecular pathways and locally produced factors. Here, we review the central role of liver APCs in the regulation of hepatic immune function and also consider how recent insights may be applied in strategies to target liver tolerance for disease therapy.

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Figure 1: Metabolic functions of the liver, general anatomy and location of liver APCs and factors that regulate their function.
Figure 2: Mechanisms downmodulating the responsiveness of liver myeloid dendritic cells to lipopolysaccharide.
Figure 3: Functional biology of liver plasmacytoid DCs.
Figure 4: Different hepatic antigen-presenting cells use B7-H1 to promote local T cell tolerance.

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Acknowledgements

The authors' work is currently supported by US National Institutes of Health grant P01 AI81678 and the Roche Organ Transplantation Research Foundation (874,279,717) (to A.W.T.) and by DFG grants SFB 704, SFB TR57, GRK 804 and SFB 670 (to P.A.K.).

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  1. Department of Surgery, and the Department of Immunology, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, 15261, Pennsylvania, USA

    Angus W. Thomson

  2. Institutes of Molecular Medicine and Experimental Immunology, University Hospital Bonn, 53105, Bonn, Germany

    Percy A. Knolle

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Glossary

Oral tolerance

The immunological mechanism whereby the mucosal immune system maintains unresponsiveness to antigens in the mucosal environment that might otherwise induce undesired immune responses.

Portal venous tolerance

The induction of peripheral tolerance following portal venous delivery of antigen (most commonly alloantigen).

Reticulo-endothelial system

The general phagocytic system of the host. It is responsible for the removal and destruction of foreign material and senescent or dead host cells, such as red blood cells.

Transcytosis

The process of transport of material across a cell layer by uptake on one side of the cell into a coated vesicle. The vesicle might then be sorted through the trans-Golgi network and transported to the opposite side of the cell.

Pattern recognition receptor

(PRR). A host receptor (such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs)) that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immunity. These receptors can be membrane bound (such as TLRs) or soluble cytoplasmic receptors (such as retinoic acid-inducible gene-I, melanoma differentiation associated gene 5 or NLRs).

Glycocalyx

A carbohydrate-rich coating that covers the outside of many eukaryotic and prokaryotic cells, particularly bacteria, and which, on bacterial cells, provides a protective coat from host factors.

Pathogen-associated molecular patterns

(PAMPs). Molecular patterns that are found in pathogens but not mammalian cells. Examples include terminally mannosylated and polymannosylated compounds, which bind the mannose receptor, and various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA, which bind to Toll-like receptors.

Acute phase proteins

A group of proteins, including C-reactive protein, serum amyloid A, fibrinogen and α1-acid glycoprotein, that are secreted into the blood in increased or decreased quantities by hepatocytes in response to trauma, inflammation or disease. These proteins can be inhibitors or mediators of inflammatory processes.

Indoleamine 2,3-dioxygenase

(IDO). An intracellular haem-containing enzyme that catalyses the oxidative catabolism of tryptophan. Insufficient availability of tryptophan can lead to T cell apoptosis and anergy.

Glisson's capsule

The capsule of the liver. A layer of connective tissue that surrounds the liver and ensheathes the hepatic artery, portal vein and bile ducts within the liver.

FMS-like tyrosine kinase 3 ligand

(FLT3L). An endogenous cytokine that stimulates the proliferation of stem and progenitor cells through binding to the FLT3 receptor (a type III receptor tyrosine kinase member of the platelet-derived growth factor family). FLT3L administration substantially increases the number of dendritic cells in lymphoid and non-lymphoid tissues.

Portal-associated lymphoid tissue

(PALT). An inducible, liver-specific immune tissue that may act as a first line of defence of the lymphatic pathway, as well as a site of local induction of immunity in the liver.

Ischaemia–reperfusion injury

Cellular damage caused by the return of a blood supply to a tissue after a period of inadequate blood supply. The absence of oxygen and nutrients causes cellular damage such that restoration of the blood flow results in inflammation.

Danger-associated molecular pattern

(DAMP). As a result of cellular stress, cellular damage and non-physiological cell death, DAMPs are released from the degraded stroma (for example, hyaluronate), from the nucleus (for example, high-mobility group box 1 protein (HMGB1)) and from the cytoplasm (for example, adenosine triphosphate, uric acid, S100 calcium-binding proteins and heat-shock proteins). Such DAMPs are thought to elicit local inflammatory reactions.

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Thomson, A., Knolle, P. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 10, 753–766 (2010). https://doi.org/10.1038/nri2858

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