Hepatocytes induce Foxp3⁺ regulatory T cells by Notch signaling

The liver plays a pivotal role in maintaining immunological tolerance, although the exact molecular mechanism is still largely unknown. The induction of systemic tolerance by liver resident APCs has been attributed to peripheral deletion and to the induction of Tregs. HCs, the parenchymal cells in the liver, could function as nonprofessional APCs and interact and establish cell-cell contact with T lymphocytes. We hypothesized that HCs from healthy or regenerated livers may contribute to induction of functional Tregs. Here, we show that murine HCs induced Foxp3(+) Tregs within CD4(+) T cells in vitro, which increased in the presence of TGF-β. Interestingly, a further Foxp3(+) Treg expansion was observed if HCs were isolated from regenerated livers. Additionally, the induction of Foxp3(+) Tregs was associated with the Notch signaling pathway, as the ability of HCs to enhance Foxp3 was abolished by γ-secretase inhibition. Furthermore, HC-iTregs showed ability to suppress the proliferative response of CD4(+) T cells to anti-CD3 stimulation in vitro. Thus, HCs may play a pivotal role in the induction of tolerance via Notch-mediated conversion of CD4(+) T cells into Foxp3(+) Tregs upon TCR stimulation.