An alternative pathway of NF-kappaB activation results in maturation and T cell priming activity of dendritic cells overexpressing a mutated IkappaBalpha.
Maturation of dendritic cells (DC) is a critical step in the induction of T cell responses and depends on the activation of NF-kappaB transcription factors. Therefore, inhibition of NF-kappaB 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 IkappaBalpha acting as a superrepressor of the classical NF-kappaB pathway (s-rIkappaB DC) to investigate the consequences of NF-kappaB inhibition on the ability of DC to prime T cell responses. Upon in vitro LPS activation, maturation of s-rIkappaB 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-alpha. In contrast, after injection, s-rIkappaB 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-rIkappaB 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-rIkappaB DC undergo efficient maturation upon prolonged contact with activated T cells via the alternative pathway of NF-kappaB activation triggered at least partly by lymphotoxin beta receptor ligation and involving processing of p100/RelB complexes.
Moore
Fabrice
F
Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium.
Buonocore
Sofia
S
Aksoy
Ezra
E
Ouled-Haddou
Najate
N
Goriely
Stanislas
S
Lazarova
Elena
E
Paulart
Frédéric
F
Heirman
Carlo
C
Vaeremans
Elsy
E
Thielemans
Kris
K
Goldman
Michel
M
Flamand
Véronique
V
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II; D020672:I-kappa B Proteins / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha