Effective antigen presentation by dendritic cells is NF-kappaB dependent: coordinate regulation of MHC, co-stimulatory molecules and cytokines.
Antigen presentation is a key rate-limiting step in the immune response. Dendritic cells (DC) are the most potent antigen-presenting cells for naive T cells, due to their high expression of MHC and co-stimulatory molecules, but little is known about the biochemical pathways that regulate this function. We here demonstrate that monocyte-derived mature DC can be infected with adenovirus at high efficiency (>95%) and that this procedure can be used to dissect out which pathways are essential for inducing DC antigen presentation to naive T cells. Using adenoviral transfer of the endogenous inhibitor of NF-kappaB, IkappaBalpha, we show that DC antigen presentation is NF-kappaB dependent. The mechanism for this is that NF-kappaB is essential for three aspects of antigen-presenting function: blocking NF-kappaB coordinately down-regulates HLA class II, co-stimulatory molecules like CD80, CD86 and CD40, and immuno-stimulatory cytokines like IL-12 and tumor necrosis factor-alpha. In contrast adhesion molecules are up-regulated after infection with the adenovirus transferring IkappaBalpha, indicating that NF-kappaB also regulates the duration of T cell-DC interaction. These results establish NF-kappaB as an effective target for blocking DC antigen presentation and inhibiting T cell-dependent immune responses, and this finding has potential implications for the development of therapeutic agents for use in allergy, autoimmunity and transplantation.
Yoshimura
S
S
Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK.
Bondeson
J
J
Foxwell
B M
BM
Brennan
F M
FM
Feldmann
M
M
D000256:Adenoviridae / Q000235:genetics; D017951:Antigen Presentation; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D005822:Genetic Vectors; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D016207:Cytokines; D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha