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An Alternative Pathway of NF-B Activation Results in Maturation and T Cell Priming Activity of Dendritic Cells Overexpressing a Mutated IB¹

Fabrice Moore^*, Sofia Buonocore^*, Ezra Aksoy^*, Najate Ouled-Haddou^*, Stanislas Goriely^*, Elena Lazarova^*, Frédéric Paulart^*, Carlo Heirman, Elsy Vaeremans, Kris Thielemans, Michel Goldman^* and Véronique Flamand^2,*

^* Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium; and Laboratory of Physiology, Medical School of Vrije Universiteit, Brussels, Belgium

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

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The Institute for Medical Immunology is sponsored by the government of the Walloon Region and GlaxoSmithKline Biologicals. This study was also supported by the Fonds National de la Recherche Scientifique (FNRS, Belgium) and an Interuniversity Attraction Pole of the Belgian Federal Science Policy. F.M. is supported by a Formation à la Recherche dans l’Industrie et dans l’Agriculture grant from FNRS, S.B. is a scientific collaborator of the FNRS, S.G. is a postdoctoral fellow of FNRS, and V.F. is a research fellow of FNRS.

² Address reprint requests to Dr. Véronique Flamand, Institute of Medical Immunology, 8 rue A. Bolland, B-6041 Gosselies, Belgium. E-mail address: vflamand{at}ulb.ac.be

³ Abbreviations used in this paper: DC, dendritic cell; BM-DC, bone marrow-derived DC; Ctrl DC, control-transduced DC; eGFP, enhanced GFP; IKK, IB kinase; LN, lymph node; LTR, lymphotoxin receptor; Pam₃CSK₄, S-[2.3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-Lys₄-OH) trihydrochloride; poly(I:C), polyinosine-polycytidylic acid; s-rIB, superrepressor of the classical NF-B pathway; WCE, whole cell extract; MEF, mouse embryonic fibroblast; LIGHT, homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for HVEM on T cells.

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