title: Dendritic cells require NIK for CD40-dependent cross-priming of CD8+ T cells.
abstract: Dendritic cells (DCs) link innate and adaptive immunity and use a host of innate immune and inflammatory receptors to respond to pathogens and inflammatory stimuli. Although DC maturation via canonical NF-κB signaling is critical for many of these functions, the role of noncanonical NF-κB signaling via the serine/threonine kinase NIK (NF-κB-inducing kinase) remains unclear. Because NIK-deficient mice lack secondary lymphoid organs, we generated transgenic mice with targeted NIK deletion in CD11c(+) cells. Although these mice exhibited normal lymphoid organs, they were defective in cross-priming naive CD8(+) T cells following vaccination, even in the presence of anti-CD40 or polyinosinic:polycytidylic acid to induce DC maturation. This impairment reflected two intrinsic defects observed in splenic CD8(+) DCs in vitro, namely antigen cross-presentation to CD8(+) T cells and secretion of IL-12p40, a cytokine known to promote cross-priming in vivo. In contrast, antigen presentation to CD4(+) T cells was not affected. These findings reveal that NIK, and thus probably the noncanonical NF-κB pathway, is critical to allow DCs to acquire the capacity to cross-present antigen and prime CD8 T cells after exposure to licensing stimuli, such as an agonistic anti-CD40 antibody or Toll-like receptor 3 ligand.
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Anand K
authors.initials: AK
authors.lastname: Katakam
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Hans
authors.initials: H
authors.lastname: Brightbill
authors.affiliation: Department of Cancer Immunology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Christian
authors.initials: C
authors.lastname: Franci
authors.affiliation: Department of Mouse Genetics, Genentech Inc., South San Francisco, CA 94080.
authors.forename: Chung
authors.initials: C
authors.lastname: Kung
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Victor
authors.initials: V
authors.lastname: Nunez
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Charles
authors.initials: C
authors.lastname: Jones
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Ivan
authors.initials: I
authors.lastname: Peng
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Surinder
authors.initials: S
authors.lastname: Jeet
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Department of Cancer Immunology, Genentech Inc., South San Francisco, CA 94080; mellman.ira@gene.com caustin@gene.com.
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
authors.affiliation: Department of Cancer Immunology, Genentech Inc., South San Francisco, CA 94080;
authors.forename: Lélia
authors.initials: L
authors.lastname: Delamarre
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080; mellman.ira@gene.com caustin@gene.com.
authors.forename: Cary D
authors.initials: CD
authors.lastname: Austin
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D039521:CD11c Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000378:metabolism*; D017353:Gene Deletion; D019426:Integrases / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D039521:CD11c Antigen; D019013:CD40 Antigens; D019426:Integrases; D053762:Interleukin-12 Subunit p40; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C045073:Cre recombinase
keywords: CD8 T cells; NIK; antigen cross-presentation; cross-priming; dendritic cells