Bcl6 Negatively Regulates Dendritic Cell Function By Suppressing IL-6 Production In Autoimmune Disease

Bcl6 is a master regulator of humoral immunity and B-cell lymphomagenesis.Bcl6 was first identified as a proto-oncogene frequently expressed in nonHodgkin's lymphoma as a result of chromosomal translocations.Bcl6 protein was found to be highly expressed in germinal center B cells,which led to the conclusion that many B cell lymphomas begin as germinal center B cells that then acquire dysregulated Bcl6 expression,new studies have now shown that Bcl6 is a master regulator of Tfh differentiation,Bcl6 negatively regulates macrophage proliferation by suppressing autocrine IL-6 production.Whereas much research has focused on its regulation and function in germinal center B-and T-cells,the role of Bcl-6 in regulating the functions of innate immune cells is not clear,the role of Bcl6 in DCs remains unclear,deletion of Bcl6 specifically in DCs was achieved by crossing conditional knockout mice with a GD11c-Cre transgenic mouse line.So we focused on researching the role of Bcl6 in DCs.We report here that conditionally knockout Bcl6 in DCs in mice promotes the autoimmune disease EAE,an animal model for MS,disease of EAE was induced by intra-dermal immunization with MOG in complete Freund's adjuvant,we found that deletion of Bcl6 specifically in DCs drives the differentiation of the Th17 subset of helper T cells in EAE mice,Bone marrow-derived DCs(BMDCs)were generated and used to study the maturation profile of these cells in response to TLR4 ligand stimulation or their cytokine production,Moreover,we found that lack of Bcl6 specifically in DCs did not affect the spontaneous,TLR4-induced maturation and activation of BMDCs but affect their cytokine production,we found that IL-6 markedly increased in Bcl6 deficient compared with Bcl6sufficient BMDCs,which can drive the differentiation of the Th17 subset of helper T cells.Our results identify Bcl6 can inhibit DCs secrete a greater amount of proinflammatory cytokine IL-6 and promote the differentiation of the Th17 subset of helper T cells,which can result to the autoimmune disease EAE.Whereas,how DC-derived signals regulate DCs produce cytokine IL-6 remains unclear.A previous study indicate the positive role of IKB-? in the TLR/IL-1R-mediated expression of IL-6.IKB-?,an atypical IKB-? family member and transcriptional coactivator required for the selective expression of a subset of NF-?B target genes,is a key activator of the il-6 gene.Furthermore,our results showed that Bcl6-/-BMDCs can produce more IL-6 because of the increased transcriptional activation of IKB-?,but not the effect on the production of IKB-?.Moreover Bcl6 protein can bind to IKB-? protein and inhibit the transcriptional function of IKB-?,so the expression of IL-6 was inhibited.Our findings suggest that Bcl6 may be a potential target in treating EAE,and also provides guidance for clinical medication.Our research may provide a promising immunotherapy for MS in humans.Moreover,our findings suggest that Bcl6 plays an important role in the negative regulation of DC-mediated immune responses.Therefore,molecular targeting of Bcl6 would be an attractive approach for the development of more effective DC vaccines and the new tumor vaccines in tumor immunotherapy.