An alternative pathway of NF-κB activation results in maturation and T cell priming activity of dendritic cells overexpressing a mutated IκBα

Maturation of dendritic cells (DC) is a critical step in the induction of T cell responses and depends on the activation of NF-kappa B transcription factors. Therefore, inhibition of NF-kappa B 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 I kappa B alpha acting as a superrepressor of the classical NF-kappa B pathway (s-rI kappa B DC) to investigate the consequences of NF-kappa B inhibition on the ability of DC to prime T cell responses. Upon in vitro LPS activation, maturation of s-rI kappa B 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-rI kappa B 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-rI kappa B 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-rI kappa B DC undergo efficient maturation upon prolonged contact with activated T cells via the alternative pathway of NF-kappa B activation triggered at least partly by lymphotoxin beta receptor ligation and involving processing of p100/RelB complexes.