Hepatocytes Contribute to Immune Regulation in the Liver by Activation of the Notch Signaling Pathway in T Cells

Abstract

The “liver tolerance effect” has been attributed to a unique potential of liver-resident nonprofessional APCs including hepatocytes (HCs) to suppress T cell responses. The exact molecular mechanism of T cell suppression by liver APCs is still largely unknown. In mice, IL-10–dependent T cell suppression is observed after Th1-mediated hepatitis induced by Con A. In this study, we show that HCs, particularly those from regenerating livers of Con A–pretreated mice, induced a regulatory phenotype in naive CD4+ T cells in vitro. Using reporter mice, we observed that these T regulatory cells released substantial amounts of IL-10, produced IFN-γ, failed to express Foxp3, but suppressed proliferation of responder T cells upon restimulation with anti-CD3 mAb. Hence, these regulatory cells feature a similar phenotype as the recently described IL-10–producing Th1 cells, which are generated upon activation of Notch signaling. Indeed, inhibition of γ-secretase and a disintegrin and metalloproteinase 17 but not a disintegrin and metalloproteinase 10, respectively, which blocked Notch activation, prevented IL-10 secretion. HCs from Con A–pretreated mice showed enhanced expression of the Notch ligand Jagged1 and significantly increased receptor density of Notch1 on CD4+ T cells. However, HCs from Con A–pretreated IFN regulatory factor 1−/− mice, which cannot respond to IFN-γ, as well as those from IFN-γ−/− mice failed to augment IL-10 production by CD4+ T cells. In conclusion, it seems that HCs fine-tune liver inflammation by upregulation of Jagged1 and activation of Notch signaling in Th1 cells. This mechanism might be of particular importance in the regenerating liver subsequent to Th1-mediated hepatitis.

Immunology of hepatic diseases during pregnancy

“…This socalled liver tolerance effect has been demonstrated most impressively in experimental transplantation settings, which not only demonstrated immune privilege towards the liver allograft but also towards co-transplanted organs from the same donor [23]. The local and systemic immune tolerogenic effect seems to be established by specialized liver resident nonconventional antigen-presenting cells (APCs) such as liver sinusoidal endothelial cells [20], hepatic stellate cells [21], and hepatocytes [24][25][26]. These non-conventional APCs incompletely activate T lymphocytes thereby inducing T cell anergy or active tolerogenicity rather than T cell effector functions.…”

Notch Signaling in T Helper Cell Subsets: Instructor or Unbiased Amplifier?

“…Although the key Treg transcription factor Foxp3 is a direct Notch target (89), the role of Notch in Tregs seems rather complex, because targeting of DLL4 or Treg-specific components of the Notch pathway was associated with an increase of Tregs in in vivo autoimmune models (49, 90, 91). Moreover, hepatocytes and plasmacytoid DCs can induce IL-10 production in T cells via Jagged1 and DLL4, respectively (85, 92, 93). Finally, the finding that the absence of Notch receptors on T cells or DLL4 on lymph node stromal cells resulted in a deficiency of Tfh cells (94, 95), implicates Notch signaling in Tfh cell differentiation.…”

DAP12 Deficiency in Liver Allografts Results in Enhanced Donor DC Migration, Augmented Effector T Cell Responses and Abrogation of Transplant Tolerance

“…These include professional and non-professional antigen (Ag)-presenting cells (APC), i.e. dendritic cells (DC) and hepatic macrophages (Kupffer cells) (12, 13), sinusoid-lining endothelial cells (14, 15), hepatic stellate cells (16, 17), and hepatocytes (18). There is strong evidence that these hepatic APC play important roles in immune regulation and tolerance induction (10).…”

“…Molecular mechanisms whereby hepatic APCs regulate/inhibit T cell responses include the expression of B7 homologue 1 (B7-H1) (14, 34, 36, 37), IL-10 (38, 39), FasL (40, 41), the Notch ligand Jagged 1 (18), CD39 (31) and DNAX-activating protein of 12kDa (DAP12) (42). DAP12 is a homodimeric immunoreceptor tyrosine-based activation motif (ITAM)-bearing transmembrane adaptor protein that is highly expressed in lymphoid tissues and the lung and to a much lesser degree in whole liver tissue (43, 44).…”