Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products

Ingrid Dumitriu, Paramita Baruah, Barbara Valentinis, Reinhard E Voll, Martin Herrmann, Peter P Nawroth, Bernd Arnold, Marco E Bianchi, Angelo A Manfredi, Patrizia Rovere-Querini

Research output: Contribution to journalArticlepeer-review

398 Citations (Scopus)


High mobility group box 1 (HMGB1) is an abundant and conserved nuclear protein that is released by necrotic cells and acts in the extracellular environment as a primary proinflammatory signal. In this study we show that human dendritic cells, which are specialized in Ag presentation to T cells, actively release their own HMGB1 into the extracellular milieu upon activation. This secreted HMGB1 is necessary for the up-regulation of CD80, CD83, and CD86 surface markers of human dendritic cells and for IL-12 production. The HMGB1 secreted by dendritic cells is also required for the clonal expansion, survival, and functional polarization of naive T cells. Using neutralizing Abs and receptor for advanced glycation end product-deficient (RAGE(-/-)) cells, we demonstrate that RAGE is required for the effect of HMGB1 on dendritic cells. HMGB1/RAGE interaction results in downstream activation of MAPKs and NF-kappaB. The use of an ancient signal of necrosis, HMGB1, by dendritic cells to sustain their own maturation and for activation of T lymphocytes represents a profitable evolutionary mechanism.

Original languageEnglish
Pages (from-to)7506-15
Number of pages10
JournalJournal of Immunology
Issue number12
Publication statusPublished - 15 Jun 2005


  • Active Transport, Cell Nucleus/physiology
  • CD4-Positive T-Lymphocytes/cytology
  • Cell Differentiation/physiology
  • Cell Proliferation
  • Cell Survival/physiology
  • Cells, Cultured
  • Clone Cells
  • Coculture Techniques
  • Cytosol/metabolism
  • Dendritic Cells/cytology
  • Extracellular Signal-Regulated MAP Kinases/physiology
  • Extracellular Space/metabolism
  • Growth Inhibitors/pharmacology
  • HMGB1 Protein/metabolism
  • Humans
  • Immune Sera/pharmacology
  • Interleukin-12/biosynthesis
  • Lymphocyte Activation/physiology
  • NF-kappa B/physiology
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic/metabolism
  • Resting Phase, Cell Cycle/physiology
  • T-Lymphocyte Subsets/cytology
  • Th1 Cells/cytology
  • p38 Mitogen-Activated Protein Kinases/metabolism


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