The role of chemokines in the recruitment of lymphocytes to the liver

Abstract

Chemokines direct leukocyte trafficking and positioning within tissues, thus playing critical roles in regulating immune responses and inflammation. The chemokine system is complex, involving interactions between multiple chemokines and their receptors that operate in combinatorial cascades with adhesion molecules. The involvement of multiple chemokines and chemokine receptors in these processes brings flexibility and specificity to recruitment. The hepatic vascular bed is a unique low-flow environment through which leukocytes are recruited to the liver during homeostatic immune surveillance and in response to infection or injury. The rate of leukocyte recruitment and the nature of cells recruited through the sinusoids in response to inflammatory signals will shape the severity of disease. At one end of the spectrum, fulminant liver failure results from a rapid recruitment of leukocytes that leads to hepatocyte destruction and liver failure; at the other end, diseases such as chronic hepatitis C infection may progress over many years from hepatitis to fibrosis and cirrhosis. Chronic hepatitis is characterized by a T lymphocyte-rich infiltrate and the nature and outcome of hepatitis will depend on the T cell subsets recruited, their activation and function within the liver. Different subsets of effector T cells have been described based on their secretion of cytokines and specific functions. These include Th1 and Th2 cells, and more recently Th17 and Th9 cells, which are associated with different types of immune response and which express distinct patterns of chemokine receptors that promote their recruitment under particular conditions. The effector function of these cells is balanced by the recruitment of regulatory T cells that are able to suppress antigen-specific effectors to allow resolution of immune responses and restoration of immune homeostasis. Understanding the signals that are responsible for recruiting different lymphocyte subsets to the liver will elucidate disease pathogenesis and open up new therapeutic approaches to modulate recruitment in favor of resolution rather than injury.

Fig. 1

Schematic diagram of the G protein-coupled receptor. Chemokine receptors are seven-transmembrane molecules coupled to heterotrimeric G proteins. When the chemokine interacts with its receptor, the β- and γ-subunits are assembled into βγ-dimers that act as functional units. The α-subunits bind guanine nucleotides, and are active when GTP is bound. The G proteins are usually classified into four classes, α_i, α_s, α_q and α_12/13, by the nature of their α-subunit. Chemokine receptors can signal through different Gα-protein families, leading to distinct transduction pathways and downstream biological effects. Adapted from Viola and Luster [89].

Fig. 2

Leukocyte adhesion cascades in hepatic sinusoid. Chemokines are critical factors in regulating lymphocyte recruitment from the blood into the liver. Leukocyte extravasation into tissue involves multiple steps. First, lymphocytes are captured, bringing the flowing cell into contact with the vessel wall, to interact with the endothelium. Second, triggering involves chemokines which are immobilized on the endothelial glycocalyx that activate chemokine receptors on leukocytes, resulting in integrin binding to endothelial ligands such as ICAM-1 and VCAM-1. During this stage, the leukocyte adheres on the vessel wall. Finally transendothelial migration into tissue occurs, which involves chemokines. Once in tissue, the cell follows chemokine gradients to sites of inflammation, using chemokine-mediated changes in the actin cytoskeleton to propel migration. CXCR = Chemokine (C-X-C motif) receptor; ICAM-1 = intercellular cell adhesion molecule 1; VCAM-1 = vascular cell adhesion molecule 1; VAP-1 = vascular adhesion protein-1; CXCR3 ligands = MIG, IP-10, I-TAC.

Fig. 3

T cell lineage and balance between T reg and Th1, Th2, Th17 and Th9. Cytokine-mediated amplification of effector CD4+ Th1, Th2, Th17 and Th9 cells. After being activated, naive T cells differentiate into distinct CD4+ helper T cell subsets depending on the cytokine milieu, which drives a program of differentiation that includes the induction of key transcription factors as well as specific chemokine receptors. Th1 cells express inflammatory type chemokine receptors CCR5 and CXCR3, Th2 cells express CCR4 and CCR8, and the recently discovered Th17 cells express CCR4, CCR6 and CXCR3. Th9 subsets were demonstrated recently from Th2 cells lineage when they were stimulated by IL-4 and TGF-β. Naturally occurring, thymic-derived T_reg maintain the immune tolerance and prevent excessive damage during infection and inflammation by controlling these T effector cells.

Fig. 4

Regulatory and effector T cell recruitment to hepatic inflammation. During hepatic inflammation, liver-resident DCs sample foreign antigen and carry it to local portal lymph nodes for presentation to naive T cells recruited via high endothelial venules of lymph nodes. Following antigen presentation, different types of T effector and T regulatory cells leave the nodes and drain back to systemic circulation before being recruited into the liver and the site of injury or inflammation via low-flow hepatic sinusoidal endothelial vascular bed. Local antigen presentation by epithelial and endothelial cells to naive T cells in the liver usually results in immunological tolerance, although microenvironmental signals form cytokines, and APCs are be important in maintaining inflammation and a polarized local immune response [121 122 123].