The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation.
The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation.
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Notch配体DLL4定义了人类树突状细胞调节Th1和Th17分化的能力
DOI：
10.4049/jimmunol.1501310
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发表时间：
2016-02-01
期刊：
影响因子：
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通讯作者：
Zhang Y
中科院分区：
文献类型：
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作者：
Meng L;Bai Z;He S;Mochizuki K;Liu Y;Purushe J;Sun H;Wang J;Yagita H;Mineishi S;Fung H;Yanik GA;Caricchio R;Fan X;Crisalli LM;Hexner EO;Reshef R;Zhang Y;Zhang Y
Notch信号调节多种辅助性CD4 + T细胞程序。我们最近已经证明，树突状细胞（DC）表达的Notch配体DLL4是关键的同种异体反应性T细胞反应和诱导小鼠移植物抗宿主病。然而，鼠DLL4 + DC的人对应物尚未被检查。我们报告了人DLL4 + DC的鉴定及其在调节Th1和Th17分化中的关键作用。来自健康供体外周血（PB）的CD1c + DC和浆细胞样DC（pDC）不表达DLL4。相比之下，接受异基因造血干细胞移植的患者的DLL4 + CD1c + DCs是健康供体的16倍。在TLR信号传导激活后，健康供体来源的CD1c + DCs显著上调DLL4，pDCs在较小程度上也是如此。活化的DLL4 + DC比未刺激的PB DC能够更好地促进Th1和Th17分化。使用中和抗体阻断DLL4降低了用DLL4 + DC刺激的T细胞中的Notch信号传导，并且其减少了Th1和Th17细胞的产生。NF-κ B和STAT 3在人DC中诱导DLL4是至关重要的。有趣的是，STAT3直接激活DLL4转录，并且单独抑制STAT3足以减少活化的PB DC中的DLL4。因此，DLL4是人循环DC的独特功能分子，其对于指导Th1和Th17分化至关重要。这些发现确定了人类炎症性疾病的治疗干预途径，如异基因造血干细胞移植后的移植物抗宿主病、自身免疫和肿瘤免疫。
Notch signaling regulates multiple helper CD4+ T cell programs. We have recently demonstrated that dendritic cells (DCs) expressing the Notch ligand DLL4 are critical for eliciting alloreactive T cell responses and induction of graft-versus-host disease in mice. However, the human counterpart of murine DLL4+ DCs has yet to be examined. We report the identification of human DLL4+ DCs and their critical role in regulating Th1 and Th17 differentiation. CD1c+ DCs and plasmacytoid DCs (pDCs) from the peripheral blood (PB) of healthy donors did not express DLL4. In contrast, patients undergoing allogeneic hematopoietic stem cell transplantation had a 16-fold more DLL4+CD1c+ DCs than healthy donors. Upon activation of TLR signaling, healthy donor-derived CD1c+ DCs dramatically upregulated DLL4, as did pDCs to a lesser extent. Activated DLL4+ DCs were better able to promote Th1 and Th17 differentiation than unstimulated PB DCs. Blocking DLL4 using a neutralizing Ab decreased Notch signaling in T cells stimulated with DLL4+ DCs, and it reduced the generation of Th1 and Th17 cells. Both NF-κB and STAT3 were crucial for inducing DLL4 in human DCs. Interestingly, STAT3 directly activated DLL4 transcription and inhibiting STAT3 alone was sufficient to reduce DLL4 in activated PB DCs. Thus, DLL4 is a unique functional molecule of human circulating DCs critical for directing Th1 and Th17 differentiation. These findings identify a pathway for therapeutic intervention for inflammatory disorders in humans, such as graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, autoimmunity, and tumor immunity.