title: NIK signaling in dendritic cells but not in T cells is required for the development of effector T cells and cell-mediated immune responses.
abstract: 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 T(H)17 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(H)1 and T(H)17 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.
authors.affiliation: Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Janin
authors.initials: J
authors.lastname: Hofmann
authors.forename: Florian
authors.initials: F
authors.lastname: Mair
authors.forename: Melanie
authors.initials: M
authors.lastname: Greter
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
mesh_terms: D000818:Animals; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007111:Immunity, Cellular / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D017346:Protein Serine-Threonine Kinases; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000097782:NF-kappaB-Inducing Kinase