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  • Review Article
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Hepatic T cells and liver tolerance

Nature Reviews Immunology volume 3, pages 51–62 (2003)Cite this article

Key Points

  • The liver is perfused by a mixture of arterial blood and blood from the intestines carrying food antigens. In the liver, blood flows through sinusoids lined with a distinctive endothelium that lacks a basement membrane and is perforated by clusters of holes (fenestrations). The sinusoidal spaces contain a large macrophage population, known as Kupffer cells.

  • The liver lymphocytes are enriched in natural killer (NK) cells, natural killer T (NKT) cells and apoptotic T cells, many of which are derived from circulating CD8+ T cells.

  • Dendritic-cell precursors traffic through the liver, but resident liver cells, including Kupffer cells, liver sinusoidal endothelial cells and hepatocytes, might be involved in antigen presentation also.

  • Presentation of antigen in the liver can result in either T-cell priming or T-cell tolerance. The liver can impose tolerance by T-cell apoptosis (mainly of CD8+ T cells) or by the induction of a regulatory phenotype (mainly of CD4+ T cells).

  • An important pathogen of humans, hepatitis C virus, has evolved many methods of immune evasion. These include classic escape mutations, mutations that create antagonistic peptides, functional inactivation of T cells (known as 'stunning') and inactivation of NK cells.

  • Hepatocytes express CD95 (FAS), a death receptor that is upregulated during inflammation. This predisposes the liver to damage whenever FAS-ligand-expressing lymphocytes are present.

Abstract

The T-cell biology of the liver is unlike that of any other organ. The local lymphocyte population is enriched in natural killer (NK) and NKT cells, which might have crucial roles in the recruitment of circulating T cells. A large macrophage population and the efficient trafficking of dendritic cells from sinusoidal blood to lymph promote antigen trapping and T-cell priming, but the local presentation of antigen causes T-cell inactivation, tolerance and apoptosis. These local mechanisms might result from the need to maintain immunological silence to harmless antigenic material in food. The overall bias of intrahepatic T-cell responses towards tolerance might account for the survival of liver allografts and for the persistence of some liver pathogens.

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Figure 1: The inputs, outputs and main functions of the liver.
Figure 2: The hepatic microenvironment.
Figure 3: The cytokine/chemokine cascade through which NK cells recruit T cells.
Figure 4: Trafficking and interactions of dendritic cells in the liver, controlled by chemokines.
Figure 5: Induction of T-cell tolerance by interaction of T cells with liver sinusoidal endothelial cells.
Figure 6: An hypothesis to explain how the tolerant state of the liver is reversed, resulting in T-cell priming and immunity.

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Acknowledgements

I would like to thank A. Livingstone, P. Knolle and R. Pierce for discussions and for constructive criticism of the manuscript, and the National Institutes of Health for research support.

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  1. Department of Microbiology and Immunology, The David H Smith Center for Vaccine Biology and Immunology, The University of Rochester, Rochester, 14642, New York, USA

    Ian Nicholas Crispe

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DATABASES

Entrez

hepatitis A virus

hepatitis B virus

hepatitis C virus

Listeria monocytogenes

mouse hepatitis virus

Mycobacterium tuberculosis

LocusLink

APAF1

B220

caspase-8

caspase-9

CCL3

CCL21

CCR1

CCR5

CCR7

CD1d

CD2

CD7

CD8α

CD11C

CD25

CD40

CD56

CD69

CD80

CD86

CD95

CTLA4

CXCL9

FLIP

ICAM1

ICAM2

IFN-α/β

IFN-γ

IL-2

IL-2Rβ

IL-4

IL-6

IL-10

IL-12

IL-15

LFA1

NK1.1

RAG1

RAG2

TLR4

TNF

TNFR1

VAP1

VCAM1

FURTHER INFORMATION

The Liver Biology and Pathobiology

Glossary

SINUSOID

A blood-filled space that lacks the anatomy of a capillary. Sinusoids generally contain slow-flowing blood, which facilitates cellular interactions. Such vessels are found in the bone marrow and in the liver.

POLYPROTEIN

A large protein that must be cleaved to yield many functional proteins. The ten proteins of hepatitis C virus are synthesized as a single polyprotein.

LIVER SINUSOIDAL ENDOTHELIAL CELLS

(LSECs). These cells form the lining endothelium of the hepatic sinusoids. They have unusual morphology (with many small holes and no basement membrane) and unusual properties as antigen-presenting cells (a strong predisposition towards the induction of tolerance, despite the expression of many co-stimulatory molecules).

SIEVE PLATE

A cluster of small holes (fenestrae) in a liver sinusoidal endothelial cell, which is believed to facilitate diffusion between the hepatic sinusoid and the underlying space of Disse, which is where solutes can interact with hepatocytes.

KUPFFER CELLS

The macrophages of the liver. These cells are derived from blood monocytes, and they phagocytose particles, including bacteria, that enter the liver sinusoids.

CROSS-PRESENTATION

The process by which exogenous antigens that are expressed by one cell are processed and presented by MHC class I molecules of another cell. Peptides derived from antigenic proteins are susceptible to this form of presentation, whereas MHC alloantigens are not. Dendritic cells and liver sinusoidal endothelial cells are particularly efficient at cross-presentation.

PASSIVE CELL DEATH

The death of T cells due to activation in the absence of sufficient survival signals, or when antigen is cleared and signals through the T-cell receptor cease.

ACTIVATION-INDUCED CELL DEATH

(AICD). The apoptosis of fully activated T cells, mediated by ligation of death receptors — such as CD95 (FAS), tumour-necrosis factor receptor 1 (TNFR1) and TNF-related apoptosis-inducing ligand receptor (TRAILR) — on their surface.

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Crispe, I. Hepatic T cells and liver tolerance. Nat Rev Immunol 3, 51–62 (2003). https://doi.org/10.1038/nri981

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