Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, 45122 Essen, Germany;
J Immunol. 2013 Dec 15;191(12):6178-90. doi: 10.4049/jimmunol.1301262. Epub 2013 Nov 13.
Liver sinusoidal endothelial cells (LSECs) are unique organ-resident APCs capable of Ag cross-presentation and subsequent tolerization of naive CD8(+) T cells. Under certain conditions, LSECs can switch from a tolerogenic to an immunogenic state and promote the development of T cell immunity. However, little is known about the mechanisms of LSECs to induce T cell immunity. In this study, we investigated whether functional maturation of LSECs can be achieved by TLR ligand stimulation and elucidated the mechanisms involved in LSEC-induced T cell immunity. We demonstrate that pretreatment of LSECs with palmitoyl-3-cysteine-serine-lysine-4 (P3C; TLR1/2 ligand) but not poly(I:C) (TLR3 ligand) or LPS (TLR4 ligand) reverted their suppressive properties to induce T cell immunity. Importantly, P3C stimulation caused functional maturation of Ag-presenting LSECs and enabled them to activate virus-specific CD8(+) T cells. The LSEC-mediated CD8(+) T cell immunity was initiated by soluble mediators, one of which was IL-12 secreted at a low but sustained level after P3C stimulation. P3C stimulation did not induce programmed death ligand 1 expression on LSECs, thereby favoring T cell proliferation and activation instead of suppression. Our data suggest that LSECs undergo maturation exclusively in response to TLR1/2 ligand stimulation and that the immunological status of LSECs was dependent upon the balance between programmed death ligand 1 and IL-12 expression. These results have implications for our understanding of liver-specific tolerance and autoimmunity and for the development of strategies to overcome T cell tolerance in situations such as chronic viral liver infections or liver cancer.
肝窦内皮细胞（LSECs）是一种独特的器官驻留 APC，能够进行 Ag 交叉呈递，并随后使幼稚 CD8(+)T 细胞耐受。在某些情况下，LSECs 可以从耐受状态转变为免疫原性状态，并促进 T 细胞免疫的发展。然而，对于 LSECs 诱导 T 细胞免疫的机制知之甚少。在本研究中，我们研究了 TLR 配体刺激是否可以使 LSECs 实现功能成熟，并阐明了涉及 LSEC 诱导 T 细胞免疫的机制。我们证明，用棕榈酰-3-半胱氨酸-丝氨酸-赖氨酸-4（P3C；TLR1/2 配体）预处理 LSECs，但不用聚肌苷酸-胞苷酸（TLR3 配体）或脂多糖（TLR4 配体），可以使它们恢复抑制性并诱导 T 细胞免疫。重要的是，P3C 刺激使 Ag 呈递 LSECs 实现功能成熟，并使它们能够激活病毒特异性 CD8(+)T 细胞。LSEC 介导的 CD8(+)T 细胞免疫是由可溶性介质启动的，其中一种介质是在 P3C 刺激后以低但持续的水平分泌的 IL-12。P3C 刺激不会诱导 LSECs 表达程序性死亡配体 1，从而有利于 T 细胞增殖和激活，而不是抑制。我们的数据表明，LSECs 仅在对 TLR1/2 配体刺激作出反应时才会发生成熟，并且 LSECs 的免疫学状态取决于程序性死亡配体 1 和 IL-12 表达之间的平衡。这些结果对于我们理解肝脏特异性耐受和自身免疫，以及在慢性病毒肝感染或肝癌等情况下开发克服 T 细胞耐受的策略具有重要意义。
