The Liver as an Immune Organ

Neutrophils

Neutrophils are the first cells that are recruited to a site of tissue injury in most bacterial infections, where they produce massive amounts of reactive oxygen species. Circulating neutrophils are rapidly recruited to the liver parenchyma from the sinusoidal space by locally produced chemokines and through interactions between cell adhesion molecules expressed on neutrophils and sinusoidal endothelial cells. Neutrophils have the plasticity to transmigrate through and between endothelial cells into the liver parenchyma. Neutrophils also play an important role in tissue repair via their capacity to phagocytose bacteria and damaged cells, as well as via production of matrix metalloproteases important in tissue remodeling ( Table 4-1 ).

Monocytes and Macrophages

Monocytes and macrophages represent the mononuclear phagocyte innate immune cells that are remarkably adaptive and responsive to the tissue microenvironment. On entering the liver, circulating monocytes can mature into macrophages and express activation markers (CD68) and further differentiate into inflammatory M1 or alternatively activated M2 phenotypes, or, as recently recognized, into intermediary forms within the M1 and M2 spectrum. The M1 phenotype is characterized by cell surface expression and production of high levels of proinflammatory cytokines. The alternately activated M2 macrophage phenotype expresses surface mannose receptor, CD206, CD163, and arginase and produces IL-10 and transforming growth factor β (TGF-β). The liver-resident macrophages, Kupffer cells, are characterized by expression of F4/80, and their role has been characterized mostly as proinflammatory in different chronic liver diseases.

Dendritic Cells

Dendritic cells (DCs) are a heterogeneous cell population that can be categorized on the basis of their origin, surface receptor expression, and functions into plasmacytoid and myeloid DCs. Depending on their maturation state, DCs can have an immature phenotype that, in response to stimuli from the tissue microenvironment or pathogens, changes to a mature phenotype characterized by changes in surface markers and T-cell stimulatory mediator (IL-12) production. The predominant DC phenotype in the liver is the immature DC that likely contributes to the tolerogenic liver environment. Furthermore, DC maturation is inhibited by TGF-β, IL-10, and prostaglandins that are all enriched in the liver. Mature DCs are the most potent antigen-presenting cell (APC) types as they potently activate T cells. Plasmacytoid DCs (CD123 ⁺ BDCA1 ⁺ ) are best equipped to recognize and respond to viral pathogen-associated molecular patterns because of their high expression of toll-like receptor 7 (TLR7) and TLR9 and their capacity to produce the highest levels of interferon-α (IFN-α) among all cell types. The myeloid DC population includes classic myeloid DCs (DCs expressing CD11c, CD13, CD33, and CD11b), type I myeloid DCs (CD1c ⁺ myeloid DCs), and type II myeloid DCs (CD141 ⁺ myeloid DCs or BDCA3 ⁺ myeloid DCs). The latter represents a small population, characterized by surface expression of BDCA3 and a high capacity to produce type II IFNs (IFN-λ species; IL-28 and IL-29).

Natural Killer Cells and Natural Killer T Cells

Natural killer (NK) and NK T (NKT) cells are lymphocytes that do not express antigen receptor with somatic diversification, which distinguishes them from T and B cells. NK cells contribute up to 50% of the human hepatic lymphocyte population, whereas they constitute between only 5% and 20% of circulating lymphocytes.

NKT cells express T-cell receptors (TCRs) and a prototypic NK-cell marker of the C-type lectin superfamily (i.e., NK1.1). The predominant TCR on NKT cells is the invariant TCR, Val4/Ja281 in the mouse and Va24/JaQ in humans. The classic invariant NKT cells recognize their specific ligands in a CD1d-restricted fashion of α-galactosylceramide triggering release of mediators. NK cells recruit NKT cells to the liver. NKT cells exert their functions in the liver through membrane-bound effector molecules, Fas ligand, and CD40, as well as through the release of death-inducing mediators such as granzyme B and perforin from intracellular vesicles.

T-Cell Populations

T cells are characterized by CD3 expression, and are typically divided into CD4 and CD8 lymphocytes on the basis of expression of these surface markers. The TCR utilization divides T cells into α/β and γ/δ T cells, of which the γ/δ T-cell population is well represented in the liver. The liver features a unique immune microenvironment that favors immune tolerance locally and systemically, and CD4 T cells contribute to this process. The type of interaction of CD4 T cells with APCs determines the development of the T cells into T _h 1 cells, T _h 2 cells, regulatory T (T _reg ) cells, or T _h 17 cells. T _h 1 CD4 T cells produce IFN-γ and TNF-α, whereas T _h 2 CD4 T cells are potent producers of IL-4, IL-10, and IL-13. CD4 T _reg cells produce IL-10 and TGF-β, and these cytokines have negative regulatory function on T _h 17 cells that produce IL-17 and IL-22.

CD8 cells represent a large proportion of hepatic T lymphocytes. CD8 T cells, for the most part, are cytotoxic lymphocytes that induce apoptosis via Fas ligand, secrete proinflammatory cytokines, and induce cytolysis. CD8 T cells are recruited to the liver independently of their antigen specificity. Most notably, CD8 T cells are critical in viral hepatitis.

T _h 17 cells and T _reg cells have opposing effects, and a regulated balance between these cells may be crucial for maintenance of immunologic stability. Disruption of this balance may lead to chronic inflammation and autoimmunity. Both T _h 17 cells and T _reg cells require TGF-β for their differentiation, but the level of cytokine required is different. Thus depending on the cytokine milieu, the differentiation of T _reg cells may be linked to the differentiation of T _h 17 cells. Recent studies in humans have revealed activated T _h 17 cells and T _h 17-related cytokines in various liver diseases, including alcoholic, viral, and autoimmune liver diseases.