1. An alternative pathway of NF-κB activation results in maturation and T cell priming activity of dendritic cells overexpressing a mutated IκBα
- Author
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Kris Thielemans, Michel Goldman, Frédéric Paulart, Carlo Heirman, Fabrice Moore, Stanislas Goriely, Elsy Vaeremans, Ezra Aksoy, Elena Lazarova, Véronique Flamand, Najate Ouled-Haddou, and Sofia Buonocore
- Subjects
Lipopolysaccharides ,T-Lymphocytes ,T cell ,Immunology ,Priming (immunology) ,Immune tolerance ,Mice ,NF-KappaB Inhibitor alpha ,MHC class I ,medicine ,Animals ,Immunology and Allergy ,Cells, Cultured ,Antigen Presentation ,MHC class II ,biology ,RELB ,Histocompatibility Antigens Class II ,NF-kappa B ,Cell Differentiation ,Dendritic Cells ,Cell biology ,IκBα ,medicine.anatomical_structure ,Gene Expression Regulation ,Mutation ,biology.protein ,Cytokines ,I-kappa B Proteins ,Lymphotoxin beta receptor - Abstract
Maturation of dendritic cells (DC) is a critical step in the induction of T cell responses and depends on the activation of NF-κB transcription factors. Therefore, inhibition of NF-κB activation has been proposed as a strategy to maintain DC in an immature stage and to promote immune tolerance. Herein, we generated murine myeloid DC expressing a mutated IκBα acting as a superrepressor of the classical NF-κB pathway (s-rIκB DC) to investigate the consequences of NF-κB inhibition on the ability of DC to prime T cell responses. Upon in vitro LPS activation, maturation of s-rIκB DC was profoundly impaired as indicated by defective up-regulation of MHC class II and costimulatory molecules and reduced secretion of IL-12 p70 and TNF-α. In contrast, after injection, s-rIκB DC had the same capacity as control DC to migrate to draining lymph node and to induce Th1- and Th2-type cytokine production in a MHC class II-incompatible host mice. Likewise, s-rIκB DC pulsed with OVA were as efficient as control DC to induce Ag-specific T cell responses in vivo. Indeed, further in vitro experiments established that s-rIκB DC undergo efficient maturation upon prolonged contact with activated T cells via the alternative pathway of NF-κB activation triggered at least partly by lymphotoxin β receptor ligation and involving processing of p100/RelB complexes.