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| 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 (DCsα-4-1BBL) not only express higher levels of CD86, CD83 and HLA-DR, when compared to the Mo-DCs matured by TNF-α, they 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 DCsα-4-1BBL showed increased secretion of Th1-type cytokines IL-12 and IFN-γ, and decreased secretion of IL-10. DCsα-4-1BBL induced much stronger proliferative responses in the MLR assay when compared with DCs derived by GM-CSF. Moreover, DCsα-4-1BBL preferentially induced Th1 responses. We have further demonstrated that anti-4-1BBL antibody stimulated nuclear translocation of NF-κB from the cytoplasm in monocytes, suggesting reverse signaling by 4-1BBL is likely responsible for mediating DCs differentiation. Collectively, we have found that reverse signaling of 4-1BBL promotes the differentiation of potent Th1-inducing DCs from human monocytes. |
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| Keywords:Costimulatory molecule, 4-1BBL, Reverse signaling, Monocytes, Dendritic cells |
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