The p50 subunit of NF-κB orchestrates dendritic cell lifespan and activation of adaptive immunity

PLoS One. 2012;7(9):e45279. doi: 10.1371/journal.pone.0045279. Epub 2012 Sep 25.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity* / drug effects
  • Animals
  • Antigen Presentation* / drug effects
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Cell Proliferation / drug effects
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / transplantation
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Gene Expression / drug effects
  • Half-Life
  • Immune Tolerance* / drug effects
  • Interferon-beta / genetics
  • Interferon-beta / immunology
  • Interleukin-1 / genetics
  • Interleukin-1 / immunology
  • Interleukin-18 / genetics
  • Interleukin-18 / immunology
  • Lipopolysaccharides / pharmacology
  • Melanoma / genetics
  • Melanoma / immunology*
  • Melanoma / pathology
  • Mice
  • NF-kappa B p50 Subunit / genetics*
  • NF-kappa B p50 Subunit / immunology
  • Skin Neoplasms / genetics
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-1
  • Interleukin-18
  • Lipopolysaccharides
  • NF-kappa B p50 Subunit
  • Interferon-beta

Grant support

This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC), Italy; Fondazione Cariplo, Italy; Ministero Università Ricerca (MIUR) e Salute, Italy; and Regione Piemonte, Italy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.