International Immunology Advance Access originally published online on August 14, 2009
International Immunology 2009 21(10):1135-1144; doi:10.1093/intimm/dxp077
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A novel approach to induce human DCs from monocytes by triggering 4-1BBL reverse signaling
1 Biotechnology Institute, Soochow University, Suzhou, Jiangsu Province, People's Republic of China
2 Cancer Biotherapy Center
3 Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province, People's Republic of China
4 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Correspondence to: Songguang Ju; E-mail: songguang_ju{at}hotmail.com / Xueguang Zhang; E-mail: xueguangzh{at}yahoo.com.cn
Dendritic cells (DCs) are responsible for the initiation of immune responses. Our study demonstrates a new pathway for generating a large quantity of stimulatory monocyte-derived DCs (Mo-DCs) from human monocytes using anti-4-1BB ligand (4-1BBL) mAb to trigger reverse signaling. The anti-4-1BBL-driven Mo-DCs (DCs
-4-1BBL) not only express higher levels of CD86, CD83 and HLA-DR, when compared with the Mo-DCs matured by tumor necrosis factor , but also exhibit a unique phenotype that expresses lower levels of PD-L1. High levels of GM-CSF, M-CSF and Flt3 ligand (FL) were found in the anti-4-1BBL-differentiation culture. Neutralizing M-CSF, GM-CSF and FL inhibited Mo-DC proliferation stimulated by anti-4-1BBL mAb, suggesting that M-CSF, GM-CSF and FL are involved in cell proliferation stimulated by anti-4-1BBL. Further analysis of the DCs-4-1BBL showed increased secretion of Th1-type cytokines IL-12 and IFN-
and decreased secretion of IL-10. DCs-4-1BBL induced much stronger proliferative responses in the mixed lymphocyte reaction assay when compared with DCs derived by GM-CSF. Moreover, DCs-4-1BBL preferentially induced Th1 responses. We have further demonstrated that anti-4-1BBL antibody stimulated nuclear translocation of NF-
B from the cytoplasm in monocytes, suggesting that reverse signaling by 4-1BBL is likely responsible for mediating DC differentiation. Collectively, we have found that reverse signaling of 4-1BBL promotes the differentiation of potent Th1-inducing DCs from human monocytes.
Keywords: 4-1BBL, co-stimulatory molecule, dendritic cells, monocytes, reverse signaling
* These authors have contributed equally to this work.
Transmitting editor: R. A. Flavell
Received 29 January 2009, accepted 19 July 2009.