The E3 Ligase FBXW7 Regulates Maturation Of Dendritic Cells

Dendritic cells(DCs)are professional antigen-presenting cells that tlay a key role in triggering immune responses.The function of DCs is closely correlated to the level of its maturation.Immature DCs,featured with strong ability of antigen processing but weak ability of antigen presenting,express low level of MHC ? and co-stimulation molecule.The pattern recognition receptors(PRR)such as Toll-like receptors(TLR)on DCs recognize the pathogen-associated molecular patterns(PAMPs),and prime the DCs maturation.DCs maturation is marked by the movement of MHC/peptide complexes to the cell membrane,upregulation of the costimulatory molecules CD80/CD86 to prime T cell activation,and expression of cytokines that drive T-cell proliferation and differentiation.Protein ubiquitination is important for the immune system in aspect of signal transduction and pathogen clearance.As a member of E3-ubiquitin-ligase,FBXW7 is reported to modulate multiple biological processes such as tumor growth,lipid metabolism,cell proliferation/differentiation,or the homeostasis of stem cells.However,the role of FBXW7 in dendritic cells is poorly clarified.In our study,we used mice which are myeloid-specific deficiency of FBXW7(Lysm-Cre+FBXW7fl/fl,refer as KO)and then established bone marrow-derived dendritic cells(BMDCs)culture system refer to Brinster's paper.We observed that although the efficiency of DCs generation was comparable,the expression of costimulatory molecules like CD86,CD80,and MHC-? were significantly decreased in KO mice after stimulation of LPS,which suggested lower maturation in KO mice.KO BMDCs expressed lower level of IL-12,IL-6 and TNF-? but higher IL-10 compared to WT DCs after LPS stimulation.And this phenomenon is also determined by ELISA.To assess the ability of KO DCs to prime naive T cells proliferation,OT-? T cells were labeled by CFSE and then co-cultured with WT or KO DCs.After 4 days,T cell proliferation was determined by flowcytometry.We found the T cells proliferation is decreased in FBXW7 KO group,indicated that compared to WT DCs,FBXW7 KO DCs could not efficiently present peptide Ag's for priming OT-? T cells.Then we determined several signaling pathway correlated with DCs maturation,NF-KB and STAT3 is downregulated in KO DCs,implied that FBXW7 exerts its function in these two signaling pathway to regulate DCs maturation.Our study suggests that E3-ubiquitin-ligase,FBXW7 controls several hallmarks of DCs function and regulates DCs maturation.It may provide a new prospective of DCs maturation study.