Noncanonical NF-κB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation

Ligation of CD40 on dendritic cells (DCs) induces early production of inflammatory mediators via canonical NF-kappa B signaling, as well as late expression of the anti inflammatory enzyme indoleamine 2,3dioxygenase (IDO) via unknown signal transduction. By selective blocking of either the canonical NF-kappa B pathway using the NEMO-binding domain peptide or the noncanonical NF-kappa B pathway by small interfering RNA, we demonstrate that IDO expression requires noncanonical NF-kappa B signaling. Also, noncanonical NF-kappa B signaling down-regulates proinflammatory cytokine production in DCs. In addition, selective activation of the noncanonical NF-kappa B pathway results in noninflammatory DCs that suppress T-cell activation and promote the development of T cells with regulatory properties. These findings reveal an important role of the noncanonical NF-kappa B pathway in the regulation of immunity.