Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
J Leukoc Biol. 2014 Oct;96(4):571-7. doi: 10.1189/jlb.2AB0613-342RR. Epub 2014 Jun 26.
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.
肝脏在维持免疫耐受方面起着关键作用，尽管确切的分子机制在很大程度上仍不清楚。肝脏驻留 APC 诱导全身耐受归因于外周细胞凋亡和 Treg 的诱导。肝实质细胞（HCs）可作为非专业 APC 与 T 淋巴细胞相互作用并建立细胞-细胞接触。我们假设来自健康或再生肝脏的 HCs 可能有助于诱导功能性 Treg。在这里，我们表明，来自体外培养的健康或再生肝脏的 HCs 可诱导 CD4+T 细胞中 Foxp3+Treg 的产生，而 TGF-β 的存在会增加 Treg 的数量。有趣的是，如果从再生肝脏中分离 HCs，则会观察到 Foxp3+Treg 的进一步扩增。此外，Foxp3+Treg 的诱导与 Notch 信号通路有关，因为 HCs 增强 Foxp3 的能力被γ-分泌酶抑制所阻断。此外，HC-iTregs 具有在体外抑制 CD4+T 细胞对抗 CD3 刺激的增殖反应的能力。因此，HCs 可能通过 Notch 介导的 TCR 刺激后 CD4+T 细胞向 Foxp3+Treg 的转化，在诱导耐受中发挥关键作用。
