Maney Nicola J, Reynolds Gary, Krippner-Heidenreich Anja, Hilkens Catharien M U
Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
J Immunol. 2014 Nov 15;193(10):4914-4923. doi: 10.4049/jimmunol.1302929. Epub 2014 Oct 6.
The capacity of dendritic cells (DC) to regulate adaptive immunity is controlled by their maturation state and lifespan. Although TNF is a well-known maturation and survival factor for DC, the role of the two TNFR, TNFR1 and TNFR2, in mediating these effects is poorly understood. By using unique TNF variants that selectively signal through TNFR1 and/or TNFR2, we demonstrate differential functions of TNFR in human monocyte-derived and blood CD1c(+) DC. Activation of TNFR1, but not TNFR2, efficiently induced DC maturation, as defined by enhanced expression of cell surface maturation markers (CD83, CD86, and HLA-DR) as well as enhanced T cell stimulatory capacity. In contrast, both TNFR1 and TNFR2 significantly protected DC against cell death, indicating that innate signals can promote DC survival in the absence of DC maturation. We further show differential activation of NF-κB signaling pathways by the TNFR: TNFR1 activated both the p65 and p52 pathways, whereas TNFR2 triggered p52, but not p65, activation. Accordingly, the p65 NF-κB pathway only played a role in the prosurvival effect of TNFR1. However, cell death protection through both TNFR was mediated through the Bcl-2/Bcl-xL pathway. Taken together, our data show that TNFR1, but not TNFR2, signaling induces DC maturation, whereas DC survival can be mediated independently through both TNFR. These data indicate differential but partly overlapping responses through TNFR1 and TNFR2 in both inflammatory and conventional DC, and they demonstrate that DC maturation and DC survival can be regulated through independent signaling pathways.
树突状细胞（DC）调节适应性免疫的能力受其成熟状态和寿命的控制。尽管肿瘤坏死因子（TNF）是DC众所周知的成熟和存活因子，但两种肿瘤坏死因子受体TNFR1和TNFR2在介导这些效应中的作用却知之甚少。通过使用选择性通过TNFR1和/或TNFR2发出信号的独特TNF变体，我们证明了TNFR在人单核细胞衍生的和血液CD1c(+) DC中的不同功能。TNFR1而非TNFR2的激活有效地诱导了DC成熟，这表现为细胞表面成熟标志物（CD83、CD86和HLA-DR）表达增强以及T细胞刺激能力增强。相比之下，TNFR1和TNFR2均能显著保护DC免于细胞死亡，这表明先天信号在DC未成熟的情况下可促进其存活。我们进一步表明TNFR对核因子κB（NF-κB）信号通路的激活存在差异：TNFR1激活p65和p52两条通路，而TNFR2仅触发p52激活，不触发p65激活。因此，p65 NF-κB通路仅在TNFR1的促存活效应中起作用。然而，通过两种TNFR实现的细胞死亡保护均是通过Bcl-2/Bcl-xL通路介导的。综上所述，我们的数据表明，TNFR1而非TNFR2的信号传导诱导DC成熟，而DC存活可通过两种TNFR独立介导。这些数据表明，在炎症性DC和传统DC中，通过TNFR1和TNFR2的反应存在差异但部分重叠，并且它们证明DC成熟和DC存活可通过独立的信号通路进行调节。
