E3 Ubiquitin Ligase Cbl-b Restrains Priming Of Pathogenic Th17 Cells Via IL-6 By Macrophages

E3(ubiquitin)ligase Cbl-b is involved in the maintenance of a balance between immunity and tolerance.Mice lacking Cbl-b gene are highly susceptible to experimental autoimmune encephalomyelitis(EAE),a Th17-mediated autoimmune disease.However,we previously demonstrated that Cbl-b does not regulate Th1 and Th17 cell differentiation,but it does inhibit Th2 cell differentiation by targeting Stat6 for ubiquitination.Therefore,how Cbl-b regulates Th17 cell development and Th17-mediated autoimmunity is currently unknown.In this study,we utilized adoptive transfer and cell type-specific Cbl-b gene knockout strains to define the role of Cbl-b in priming of pathogenic Th17 cells and Th17-mediated autoimmunity using EAE as a model.We found that mice lacking Cbl-b gene in the myeloid cells lineages(macrophages)but not T cells or dendritic cells(DCs)developed severe EAE.And Cbl-b expressed in macrophages but not in T cells or DCs was essential for the generation of pathogenic Th17 cells.Furthermore,Loss of Cbl-b resulted in up-regulation of interleukin-6(IL-6)and other pro-inflammatory cytokines induced by the signaling derived from C-type lectin receptor Dectin-2 which direct T cells to generate pathogenic Th17 cells in vitro and in vivo.Therefore,our data are the first to unveil a previously-unappreciated function for Cbl-b in the regulation of pathogenic Th17 response.