Adult Human Hepatocytes Promote CD4⁺ T-Cell Hyporesponsiveness Via Interleukin-10-Producing Allogeneic Dendritic Cells

Abstract

The success of liver cell therapy remains closely dependent on how well the infused cells can be accepted after transplantation and is directly related to their degree of immunogenicity. In this study, we investigated the in vitro immunogenic properties of isolated human hepatocytes (hHeps) and adult-derived human liver progenitor cells (ADHLPCs), an alternative cell candidate for liver cell transplantation (LCT). The constitutive expression of immune markers was first analyzed on these liver-derived cells by flow cytometry. Human liver-derived cells were then cocultured with allogeneic human adult peripheral blood mononuclear cells (PBMCs), and the resulting activation and proliferation of PBMCs was evaluated, as well as the cytokine levels in the coculture supernatant. The effect of liver-derived cells on monocyte-derived dendritic cell (MoDC) properties was further analyzed in a secondary coculture with naive CD4(+) T-cells. We report that hHeps and ADHLPCs expressed human leukocyte antigen (HLA) class I and Fas but did not express HLA-DR, Fas ligand, and costimulatory molecules. hHeps and ADHLPCs did not induce T-cell activation or proliferation. Moreover, hHeps induced a cell contact-dependent production of interleukin (IL)-10 that was not observed with ADHLPCs. The IL-10 was produced by a myeloid DC subset characterized by an incomplete mature state. Furthermore, hHep-primed MoDCs induced an antigen-independent hyporesponsiveness of naive CD4(+) T lymphocytes that was partially reversed by blocking IL-10, whereas nonprimed MoDCs (i.e., those cultured alone) did not. hHeps and ADHLPCs present a low immunogenic phenotype in vitro. Allogeneic hHeps, but not ADHLPCs, promote a cell contact-dependent production of IL-10 by myeloid DCs, which induces naive CD4(+) T-cells antigen-independent hyporesponsiveness.

Immune surveillance by the liver

“…Furthermore, contact with LSECs and hepatocytes further reduces the capacity of DCs to activate T cells (antigen-independent hyporesponsiveness). This reduced activation of T cells is due, at least in part, to the production of additional IL-10 by DCs themselves 29,78 . In addition to inducing antigen-independent hyporesponsiveness in T cells, this DC-derived IL-10 also promotes a shift from T H 1-type responses to T H 2-type responses, further suppressing cellular immunity and promoting the development of T reg cells 79 .…”

“…Additionally, a mechanism involving direct cell-cell contact between LSECs and liver DCs is implicated in the maintenance of T cell tolerance within the liver microenvironment 29 . Moreover, continual exposure to pathogen-derived molecules (such as LPS) from the gut induces the expression of additional anti-inflammatory molecules, such as IL-10, which further reduce the expression of MHCs and help reinforce the state of immune nonresponsiveness observed in the liver under basal conditions 27,34,78 . Despite this default environment of immune nonresponsiveness or tolerance, given appropriate stimulation, a robust immune response can be generated in the liver.…”

Comprehensive Screening of Cell Surface Markers Expressed by Adult‐Derived Human Liver Stem/Progenitor Cells Harvested at Passage 5: Potential Implications for Engraftment

“…One hypothesis is that donor cells could be cleared by the immune system of the recipient. Our previous studies indicated that ADHLSCs are poorly immunogenic [6, 7], but their immune profile has not yet been completely characterized. In addition, there could be some impairment in the engraftment process itself.…”

Adult human liver mesenchymal progenitor cells express phenylalanine hydroxylase

“…(28). ADHLSC do not express HLA II, FAS ligand or costimulatory molecules (29) Innate and adaptative host immune responses explain a large part of cell loss in hepatocytes transplantation (30). Safety experiments do not show any increased risk of tumorigenicity, neither in vitro with a normal growth arrest and senescence, nor in vivo after transplantation in a nude mouse model (31).…”