Immunological functions of liver sinusoidal endothelial cells

Abstract

Liver sinusoidal endothelial cells (LSECs) line the liver sinusoids and separate passenger leukocytes in the sinusoidal lumen from hepatocytes. LSECs further act as a platform for adhesion of various liver-resident immune cell populations such as Kupffer cells, innate lymphoid cells or liver dendritic cells. In addition to having an extraordinary scavenger function, LSECs possess potent immune functions, serving as sentinel cells to detect microbial infection through pattern recognition receptor activation and as antigen (cross)-presenting cells. LSECs cross-prime naive CD8 T cells, causing their rapid differentiation into memory T cells that relocate to secondary lymphoid tissues and provide protection when they re-encounter the antigen during microbial infection. Cross-presentation of viral antigens by LSECs derived from infected hepatocytes triggers local activation of effector CD8 T cells and thereby assures hepatic immune surveillance. The immune function of LSECs complements conventional immune-activating mechanisms to accommodate optimal immune surveillance against infectious microorganisms while preserving the integrity of the liver as a metabolic organ.

Figure 1

Infection accompanied by inflammation leads to maturation of dendritic cells that will cross-prime naive CD8 T cells and elicit their differentiation into short-lived effector T cells or memory T cells. Upon re-encountering antigen, central memory CD8 T cells are re-activated and through proliferation, will provide sufficient pathogen-specific T-cell progeny to contain infection. In the absence of inflammation, antigens cross-presented by immature dendritic cells will lead to clonal deletion of T cells, thus causing a hole in the TCR repertoire that may affect antiviral immunity because viral antigens often are systemically disseminated during the early phases of infection. Cross-priming by LSECs leads to naive CD8 T-cell activation, which protects these cells from deletional tolerance by immature dendritic cells and causes differentiation into memory T cells with proliferative potential. Upon combinatorial stimulation via the TCR, CD28 and the IL-12 receptor, such LSEC-primed memory T cells are re-activated and start to proliferate and differentiate into effector cells that contribute to elimination of viral and bacterial infections. IL-12, interleukin-12; LSEC, liver sinusoidal endothelial cell; TCR, T-cell receptor.

Figure 2

Conventional CD8 T-cell effector function is mediated by recognition of viral peptides presented by infected hepatocytes on MHC I molecules, thus triggering effector cell function and killing by release of perforin and granzyme B. Non-canonical CD8 T-cell effector function is initiated independently from direct recognition of infected target cells by effector CD8 T cells. Rather, cross-presentation of viral antigens released from infected hepatocytes through LSECs leads to activation of effector CD8 T cells. Such activation triggers expression and release of TNF that then acts selectively on virus-infected, but not healthy, hepatocytes to induce caspase-dependent cell death. LSEC, liver sinusoidal endothelial cell; MHC, major histocompatibility complex; TNF, tumor necrosis factor.