The Liver Works As a School to Educate Regulatory Immune Cells
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Cellular & Molecular Immunology (2013) 10, 292–302 ß 2013 CSI and USTC. All rights reserved 1672-7681/13 $32.00 www.nature.com/cmi REVIEW The liver works as a school to educate regulatory immune cells Fenglei Li1 and Zhigang Tian1,2 Because of its unique blood supply, the liver maintains a special local immune tolerogenic microenvironment. Moreover, the liver can impart this immune tolerogenic effect on other organs, thus inducing systemic immune tolerance. The network of hepatic regulatory cells is an important mechanism underlying liver tolerance. Many types of liver-resident antigen-presenting cells (APCs) have immune regulatory function, and more importantly, they can also induce the differentiation of circulating immune cells into regulatory cells to further extend systemic tolerance. Thus, the liver can be seen as a type of ‘school,’ where liver APCs function as ‘teachers’ and circulating immune cells function as ‘students.’ Cellular & Molecular Immunology (2013) 10, 292–302; doi:10.1038/cmi.2013.7; published online 22 April 2013 Keywords: liver; immune regulation; immune tolerance INTRODUCTION accepted when transplanted into hosts with a mismatched The immune system is the most important weapon used by the major histocompatibility complex (MHC) background in a body to defend itself against pathogens and unwanted self-cells, pig model of transplantation.5 Tolerance is also achieved by but abnormal immune responses sometimes cause severe intraportal antigen delivery into the liver, which can then damage to the host. Therefore, the accuracy of the immune induce systemic tolerance.6,7 Similarly, oral tolerance—the sys- system is often more important than its ability to defend. To temic tolerance induced by orally administering foreign anti- accomplish this, the first requirement is for immune cells to gens—is also dependent upon the liver.6 Under pathological distinguish between self and non-self. T cells undergo positive states, such as hepatitis viral infection, immune tolerance, and negative selection in the thymus, where the self-reactive T- rather than an immune response, is often induced in the liver.8 cell repertoire dies by apoptosis. This central prevents the There are several ways to explain why the liver is a site of immune system from retaining memory to self. However, immune tolerance. The classic hypothesis is that the liver func- many low-affinity self-reactive T cells can still escape from tions as a ‘graveyard’ for T cells. Huang et al.9 found that when the thymus and spread into the periphery.1–3 Thus, the second T-cell receptor (TCR) transgenic mice were injected with a requirement is for the immune response to maintain an appro- specific peptide for a given TCR antigen, activated T cells tra- priate level even when confronted with an enemy, as a weak veled to the liver and died. Later, anti-CD3 administration was immune response cannot effectively clear pathogens, but an also found to induce activated T-cell accumulation and apop- excessively strong immune response can lead to autoimmune tosis in the liver.10 Although this hypothesis drew the attention disease and allergy. of many immunologists, it could not explain the observation The unique systemic circulation within the liver makes it not that effector and memory cells were also generated during viral only able to obtain blood from the hepatic artery, but also infection, especially in hepatitis, and could sometimes clear the through the portal vein, the latter containing nutrients, meta- infection. bolic products, toxins and soluble antigens.4 Faced with hand- Another viable explanation for liver tolerance is its unique ling all of these components, the liver also plays a role hepatic regulatory mechanisms. From an evolutionary and dif- in metabolic detoxification. Moreover, increased evidence ferentiation perspective, the fetal liver has the same hemato- demonstrates that the liver is also an important immunoto- poietic function as bone marrow; interestingly, the latter was lerant organ. As a striking example of this, liver allografts are also found to have immune regulatory potential.11 Many types 1Hefei National Laboratory for Physical Sciences at Microscale, Hefei, China and 2Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China Correspondence: Dr ZG Tian, School of Life Sciences, University of Science and Technology of China, 443 Huangshan Road, Hefei 230027, China. E-mail: [email protected] Received: 14 February 2013; Accepted: 21 February 2013 The liver works as a school to educate regulatory immune cells FL Li and ZG Tian 293 of liver-resident nonparenchymal cells and hepatocytes can may be able to modulate immune responses in other organs present antigens and often exhibit a unique regulatory function and induce systemic immune tolerance. compared with their counterparts in other organs. These anti- The influenza virus causes respiratory tract infections and gen-presenting cells (APCs) can also interact with other cir- induces lung inflammation. Interestingly, influenza can also culating cells and endow them with regulatory function. In cause hepatitis even though no viral titers can be detected in turn, the newly induced regulatory cells can go on to induce the liver, because virus-specific cytotoxic lymphocytes (CTLs) regulatory function in other cells, even in the periphery. Thus, originally generated within the lung can encounter Kupffer resident and circulating cells work cooperatively to form a cells in the liver and induce hepatocyte apoptosis.12 A similar complex network that maintains liver tolerance. Indeed, an phenomenon has been observed between the pancreas and the increasing number of studies demonstrate that the liver func- liver, where liver-derived, ex vivo-expanded dendritic cells tions in a dramatic way to control immune responses. In this (DCs) can improve islet allograft survival.13 Taken together, review, we will discuss how the liver functions as a ‘school’ to these observations suggest that immune cells traffic between educate regulatory cells. the liver and other organs to regulate local immune responses. The liver has also been shown to interact with and induce THE LIVER EXERTS BOTH LOCAL AND SYSTEMIC immune tolerance within the central nervous system (CNS). TOLEROGENIC EFFECTS Niemann–Pick disease is characterized by excessive sphingo- Liver tolerance is not locally restricted to the liver, as crosstalk myelin buildup in the brain, and recovery of acid sphingomye- often occurs between the liver and other organs. This crosstalk linase (ASM) expression in the host is key to a cure. While regulates the extra-hepatic immune responses that finally lead intracranial delivery of an ASM-expressing vector is not viable to systemic tolerance (Figure 1). The most well-known and because ASM-specific antibodies will be produced, Cheng and accepted illustration of this is the systemic immune tolerance colleagues14 found that simultaneously delivering an ASM- induced when a liver is transplanted into a host, where to- expressing vector into both the brain and the liver promoted lerance is induced not only to the liver, but also to skin allo- tolerance to this protein and prevented antibody secretion, thus grafts cotransplanted from the same donor.5 Additionally, liver achieving an effective therapy. This suggested that the liver- allografts can survive without immunosuppressive drugs, even generated regulatory immune response toward ASM could though other organs—such as the skin, kidney and heart—are inhibit the destructive immune response occurring in the brain. rapidly rejected. Thus, liver allograft protection against donor- Experimental autoimmune encephalomyelitis is a mouse model specific skin and kidney rejection suggests that allogeneic liver of the autoimmune disease multiple sclerosis. It is induced in Normal organs after hepatic pathogen clearance pancreas pancreas pancreas skin skin skin CNS CNS CNS kidneys 2 kidneys 3 kidneys liver liver liver pancreas hearts hearts 1 hearts lung lung lung skin muscle muscle muscle LN LN LN CNS kidneys liver pancreas pancreas pancreas hearts lung skin skin skin muscle LN 4 CNS CNS CNS kidneys 5 kidneys 6 kidneys liver liver liver hearts hearts lung lung hearts lung muscle muscle LN LN muscle LN Liver infection induces systemic immune tolerance to infection Figure 1 Crosstalk between the liver and other organs can regulate immunity in other organs. Unlike other immune-privileged organs, the liver contains many types of immune cells. (1) The immune response often occurs in the liver during virus infection, transplantation, ectopic antigen expression and so on. (2) The liver can sometimes generate a positive immune response to eliminate various ‘enemies’, (3) which is followed by the generation of immune defense throughout the body. (4) Immune tolerance is more often induced, allowing foreign antigens to persist in the liver. (5) Additionally, the liver can crosstalk with other organs and regulate their immune responses, effectively inducing systemic tolerance. (6) After transferring immune tolerance from the liver to the entire body, systemic immune responses are suppressed, allowing for virus infection, tumor migration, transplant acceptance and so on. CNS, central nervous system; LN, lymph node. Cellular & Molecular Immunology The liver works as a school to educate regulatory immune cells FL Li and ZG Tian 294 the CNS and can also be controlled by liver tolerance. Liver, but APCs27 or secrete regulatory cytokines, such as