NIK-driven IL-23 production by myeloid cells is a key factor in the development of autoimmune inflammation.

NIK (Map3k14) is a central regulator of noncanonical NF-κB signaling and immune homeostasis. Mutations in this kinase are linked to autoimmune disorders, including multiple sclerosis (MS). Both germline and T cell-specific deletion of NIK had been demonstrated previously to be associated with resistance to developing experimental autoimmune encephalomyelitis (EAE), an animal model for MS. In this study, we show that NIK expression by circulating myeloid cells is crucial for EAE development. Mechanistically, we found starkly reduced priming of neuroantigen-specific T cells in the absence of NIK in CX3CR1+ cells. This reduction was associated with dysregulated expression of genes involved in antigen presentation and cell migration, as well as decreased IL-23 production. Notably, T cells primed by NIK-deficient myeloid cells regained their ability to induce EAE when incubated with IL-23 before being transferred into RagKO mice. Our data underline the crucial role of NIK in enabling myeloid cells to function effectively as antigen-presenting cells.