TLR2 Stimulation Strengthens Intrahepatic Myeloid-Derived Cell-Mediated T Cell Tolerance through Inducing Kupffer Cell Expansion and IL-10 Production
TLR2 Stimulation Strengthens Intrahepatic Myeloid-Derived Cell-Mediated T Cell Tolerance through Inducing Kupffer Cell Expansion and IL-10 Production
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TLR2 刺激通过诱导库普弗细胞扩增和 IL-10 产生增强肝内骨髓源性细胞介导的 T 细胞耐受性
DOI：
10.4049/jimmunol.1700540
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发表时间：
2018-04-01
影响因子：
4.4
通讯作者：
Lu, Mengji
中科院分区：
文献类型：
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作者：
Liu, Jia;Yu, Qing;Lu, Mengji
肝脏APC在促进肝脏免疫耐受方面发挥着关键作用。最近，我们已经证明TLR2刺激肝窦内皮细胞可以逆转其抑制特性，从而诱导T细胞免疫。然而，关于TLR2刺激如何调节其他肝脏APC的免疫功能的信息很少。在本研究中，我们研究了TLR2刺激是否影响肝内髓系细胞(IMDC)的功能，并阐明了IMDC诱导T细胞免疫的机制。我们可以证明来自C57BL/6小鼠的iMDCs能够以一种细胞接触非接触的方式有效地抑制T细胞的激活。IMDCs的抗原提呈导致了幼稚的CD8T细胞耐受。令我们惊讶的是，TLR2配体棕榈酰-3-半胱氨酸-丝氨酸-赖氨酸-4(P3C)刺激不是诱导细胞功能成熟，而是进一步增强IMDCs的抑制和耐受特性。P3C处理后，iMDCs的Kupffer细胞(KCs)数量显著增加。机制分析表明，KCs在P3C刺激的iMDCs对T细胞活化的增强抑制中是必不可少的。IMDC介导的CD8 T细胞抑制是由可溶性介质介导的，其中一种是P3C刺激后KCs分泌的IL-10。阻断IL-10可部分消除IMDC介导的T细胞抑制作用。此外，乙肝病毒颗粒对iMDCs的刺激也可以TLR2依赖的方式诱导iMDCs产生IL-10。我们的研究结果对于我们理解肝脏特异性耐受性，以及在慢性病毒性肝感染等情况下克服T细胞耐受性的策略的发展具有重要意义。
Hepatic APCs play a critical role in promoting immune tolerance in the liver. Recently, we have demonstrated that TLR2 stimulation on liver sinusoidal endothelial cells reverted their suppressive properties to induce T cell immunity. However, there is a paucity of information about how TLR2 stimulation modulates the immunological function of other hepatic APCs. In the current study, we investigated whether TLR2 stimulation influences the function of intrahepatic myeloid-derived cells (iMDCs) and elucidated the mechanisms involved in iMDC-induced T cell immunity. We could show that iMDCs from C57BL/6 mice can potently suppress T cell activation in a cell contact–independent manner. Ag presentation by iMDCs leads to naive CD8 T cell tolerance. To our surprise, instead of inducing cell functional maturation, TLR2 ligand palmitoyl-3-cysteine-serine-lysine-4 (P3C) stimulation further strengthens the suppressive and tolerogenic properties of iMDCs. After P3C administration, the population of Kupffer cells (KCs) of iMDCs dramatically increased. Mechanism analysis shows that KCs are essential for the enhanced inhibition of T cell activation by P3C-stimulated iMDCs. The iMDC-mediated CD8 T cell inhibition was mediated by soluble mediators, one of which was IL-10 secreted by KCs after P3C stimulation. IL-10 blockade could partially abolish iMDC-mediated T cell inhibition. Moreover, hepatitis B virus particle stimulation on iMDCs could also induce IL-10 production by the cells in a TLR2-dependent way. Our results have implications for our understanding of liver-specific tolerance and for the development of strategies to overcome T cell tolerance in situations such as chronic viral liver infections.