Meng Lijun, Bai Zhenjiang, He Shan, Mochizuki Kazuhiro, Liu Yongnian, Purushe Janaki, Sun Hongxing, Wang Jian, Yagita Hideo, Mineishi Shin, Fung Henry, Yanik Gregory A, Caricchio Roberto, Fan Xiaoxuan, Crisalli Lisa M, Hexner Elizabeth O, Reshef Ran, Zhang Yanyun, Zhang Yi
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200231, China; Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140; Department of Microbiology and Immunology, Temple University, Philadelphia, PA 19140;
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140; Pediatric Intensive Care Unit, Children's Hospital of Soochow University, Soochow University, Suzhou 215003, China;
J Immunol. 2016 Feb 1;196(3):1070-80. doi: 10.4049/jimmunol.1501310. Epub 2015 Dec 28.
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.
Notch信号通路调控多种辅助性CD4(+) T细胞程序。我们最近证明，表达Notch配体DLL4的树突状细胞（DCs）对于引发同种异体反应性T细胞应答以及诱导小鼠移植物抗宿主病至关重要。然而，小鼠DLL4(+) DCs在人类中的对应物尚未得到研究。我们报告了人类DLL4(+) DCs的鉴定及其在调节Th1和Th17分化中的关键作用。健康供体外周血（PB）中的CD1c(+) DCs和浆细胞样DCs（pDCs）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比健康供体多16倍。在TLR信号通路激活后，健康供体来源的CD1c(+) DCs显著上调DLL4，pDCs也有较小程度的上调。活化的DLL4(+) DCs比未刺激的PB DCs更能促进Th1和Th17分化。使用中和抗体阻断DLL4可降低用DLL4(+) DCs刺激的T细胞中的Notch信号，并减少Th1和Th17细胞的生成。NF-κB和STAT3对于在人类DCs中诱导DLL4都至关重要。有趣的是，STAT3直接激活DLL4转录，单独抑制STAT3就足以降低活化的PB DCs中的DLL4。因此，DLL4是人类循环DCs中一种独特的功能分子，对指导Th1和Th17分化至关重要。这些发现确定了一条针对人类炎症性疾病的治疗干预途径，例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。
