NIK signaling in dendritic cells but not in T cells is required for the development of effector T cells and cell-mediated immune responses

The canonical NF-κB pathway is a driving force for virtually all aspects of inflammation. Conversely, the role of the noncanonical NF-κB pathway and its central mediator NF-κB- inducing kinase (NIK) remains poorly defined. NIK has been proposed to be involved in the formation of TH17 cells, and its absence in T_H cells renders them incapable of inducing autoimmune responses, suggesting a T cell-intrinsic role for NIK. Upon systematic analysis of NIK function in cell-mediated immunity, we found that NIK signaling is dispensable within CD4⁺ T cells but played a pivotal role in dendritic cells (DCs). We discovered that NIK signaling is required in DCs to deliver co-stimulatory signals to CD4⁺ T cells and that DC-restricted expression of NIK is sufficient to restore T_H1 and T_H17 responses as well as cell-mediated immunity in NIK^-/- mice. When CD4⁺ T cells developed in the absence of NIK-sufficient DCs, they were rendered anergic. Reintroduction of NIK into DCs allowed developing NIK^-/- CD4⁺ T cells to become functional effector populations and restored the development of autoimmune disease. Therefore, our data suggest that a population of thymic DCs requires NIK to shape the formation of most αβ CD4⁺ T effector lineages during early development.