title: A nonredundant role for canonical NF-κB in human myeloid dendritic cell development and function.
abstract: The plastic role of dendritic cells (DCs) in the regulation of immune responses has made them interesting targets for immunotherapy, but also for pathogens or tumors to evade immunity. Functional alterations of DCs are often ascribed to manipulation of canonical NF-κB activity. However, though this pathway has been linked to murine myeloid DC biology, a detailed analysis of its importance in human myeloid DC differentiation, survival, maturation, and function is lacking. The myeloid DC subsets include interstitial DCs and Langerhans cells. In this study, we investigated the role of canonical NF-κB in human myeloid DCs generated from monocytes (monocyte-derived DCs [mo-DCs]) or CD34(+) progenitors (CD34-derived myeloid DCs [CD34-mDCs]). Inhibition of NF-κB activation during and after mo-DC, CD34-interstitial DC, or CD34-Langerhans cell differentiation resulted in apoptosis induction associated with caspase 3 activation and loss of mitochondrial transmembrane potential. Besides regulating survival, canonical NF-κB activity was required for the acquisition of a DC phenotype. Despite phenotypic differences, however, Ag uptake, costimulatory molecule and CCR7 expression, as well as T cell stimulatory capacity of cells generated under NF-κB inhibition were comparable to control DCs, indicating that canonical NF-κB activity during differentiation is redundant for the development of functional APCs. However, both mo-DC and CD34-mDC functionality were reduced by NF-κB inhibition during activation. In conclusion, canonical NF-κB activity is essential for the development and function of mo-DCs as well as CD34-mDCs. Insight into the role of this pathway may help in understanding how pathogens and tumors escape immunity and aid in developing novel treatment strategies aiming to interfere with human immune responses.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
authors.forename: Lianne
authors.initials: L
authors.lastname: van de Laar
authors.forename: Aniek
authors.initials: A
authors.lastname: van den Bosch
authors.forename: Sandra W
authors.initials: SW
authors.lastname: van der Kooij
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Woltman
mesh_terms: D000941:Antigens / Q000276:immunology / Q000378:metabolism; D018952:Antigens, CD34; D017209:Apoptosis / Q000276:immunology; D053148:Caspase 3 / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007801:Langerhans Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D054400:Receptors, CCR7 / Q000096:biosynthesis / Q000276:immunology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000941:Antigens; D018952:Antigens, CD34; C515370:CCR7 protein, human; D016328:NF-kappa B; D054400:Receptors, CCR7; C505407:CASP3 protein, human; D053148:Caspase 3