The p50 subunit of NF-κB orchestrates dendritic cell lifespan and activation of adaptive immunity.
Dendritic cells play a central role in keeping the balance between immunity and immune tolerance. A key factor in this equilibrium is the lifespan of DC, as its reduction restrains antigen availability leading to termination of immune responses. Here we show that lipopolysaccharide-driven DC maturation is paralleled by increased nuclear levels of p50 NF-κB, an event associated with DC apoptosis. Lack of p50 in murine DC promoted increased lifespan, enhanced level of maturation associated with increased expression of the proinflammatory cytokines IL-1, IL-18 and IFN-β, enhanced capacity of activating and expanding CD4(+) and CD8(+) T cells in vivo and decreased ability to induce differentiation of FoxP3(+) regulatory T cells. In agreement, vaccination of melanoma-bearing mice with antigen-pulsed LPS-treated p50(-/-) BM-DC boosted antitumor immunity and inhibition of tumor growth. We propose that nuclear accumulation of the p50 NF-κB subunit in DC, as occurring during lipopolysaccharide-driven maturation, is a homeostatic mechanism tuning the balance between uncontrolled activation of adaptive immunity and immune tolerance.
Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Paola
P
Larghi
Chiara
C
Porta
Elena
E
Riboldi
Maria Grazia
MG
Totaro
Lorenzo
L
Carraro
Ciriana
C
Orabona
Antonio
A
Sica
D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D006207:Half-Life; D007108:Immune Tolerance / Q000187:drug effects; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000235:genetics* / Q000276:immunology; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007375:Interleukin-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D016899:Interferon-beta