Dendritic cells in hepatitis and liver transplantation

Abstract

Dendritic cells (DCs) play a key role in innate immune responses and are also the most effective cells for the activation of T cell immunity. They acquire antigen and process it; then they display it on the cell surface bound in a noncovalent complex with human leukocyte antigen molecules of class I (human leukocyte antigens A, B, and C) and class II (human leukocyte antigen DR). These cells are subdivided into 3 main subsets: 2 called myeloid dendritic cells (mDC) or classical DCs of types 1 and 2, and 1 called plasmacytoid dendritic cells (pDCs). The mDCs process and present antigen while the pDCs also strongly respond to viral signals by secreting type 1 interferon. In the liver, all of these subsets are present. However, their relative abundance is different from the peripheral blood, and it is further modified by liver disease. It appears that in relation to T cell tolerance, both mDCs and pDCs are influenced by the liver milieu and promote T cell inactivation. However, in antiviral responses and in ischemia/reperfusion injury, where innate immune functions are more important, mDCs and pDCs have distinct roles. Liver Transplantation 23 1433-1439 2017 AASLD.

Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches

“…High co-inhibitory molecule expression by HDCs can be induced by the nucleotide-binding oligomerization domain 2 (NOD2) signaling, significantly more expressed in hepatic plasmacytoid (pDCs) than in conventional or myeloid (mDCs) dendritic cells, which is also responsible for their low IFN-α secretion (101). The CD141+ subset of mDCs, which produces IL-12 and plays a central role in antigen cross-presentation (102), have also been reported in healthy human livers to express high levels of the tolerogenic molecules immunoglobulinlike transcript 3 (ILT3) and ILT4 (103), which can inhibit T cell activation through tyrosine-based inhibitory motifs (ITIMs) contained in their cytoplasmic tails (104,105).…”

“…During viral infection, regulatory T cells are recruited into the inflamed liver and compete with effector CD8 T cells for IL-2, limiting the amplification of virus-specific T cell responses (8). Both mDCs and pDCs have been described to promote Treg proliferation through a mechanism mediated by STAT3 signaling (102,(157)(158)(159). Specifically, the expansion of Treg cells, which can inhibit T cell responses either by direct cell-cell contact or by secretion of suppressive cytokines, can be caused by plasmacytoid dendritic cells (pDCs) through an IL27-based circuit which can lead to PD-L1 expression and subsequent Treg proliferation (158,160).…”

“…Specifically, the expansion of Treg cells, which can inhibit T cell responses either by direct cell-cell contact or by secretion of suppressive cytokines, can be caused by plasmacytoid dendritic cells (pDCs) through an IL27-based circuit which can lead to PD-L1 expression and subsequent Treg proliferation (158,160). pDCs further foster T cell tolerance by stimulating IL-10 producing Tregs via an ICOS/ICOSL-mediated interaction (102,159). In parallel, mDCs can also promote Treg expansion and T cell apoptosis as a result of the cross-talk with HSCs, leading to PD-L1 up-regulation and IDO induction, and subsequent generation of immunosuppressive kynurenine compounds (161)(162)(163).…”

Circulating and Hepatic BDCA1+, BDCA2+, and BDCA3+ Dendritic Cells Are Differentially Subverted in Patients With Chronic HBV Infection

“…cDC2 represent the main blood DC population, whereas cDC1 are enriched within hepatic DCs (11). cDC1 are the most potent producers of IFN-λ in response to viruses or synthetic RNA polyI:C that induces TLR3 signaling (12, 13) and are specialized in antigen cross-presentation, therefore actively participating in the control of hepatotropic viruses (10, 14, 15).…”

Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease

“…48 The intrahepatic DC population consists of subsets that resemble immature, tolerogenic APCs that are resistant to maturation. [48][49][50][51] To a large extent, intrahepatic DCs are plasmacytoid (B220 + ) DCs (pDCs) that produce tolerogenic cytokines, such as IL-10 and IL-27, in response to LPS stimulation. 48 IL-27 signaling can then induce PD-L1 expression on hepatic pDCs via signal transducer and activator of transcription (Stat)3 signaling, leading to the generation of tolerogenic pDCs that are capable of inducing CD4 + Foxp3 + Tregs in vitro.…”