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

J Immunol. 2005 Jun 15;174(12):7506-15. doi: 10.4049/jimmunol.174.12.7506.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / physiology
  • Cell Differentiation / physiology
  • Cell Proliferation
  • Cell Survival / physiology
  • Cells, Cultured
  • Clone Cells
  • Coculture Techniques
  • Cytosol / metabolism
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Extracellular Space / metabolism
  • Growth Inhibitors / pharmacology
  • HMGB1 Protein / metabolism*
  • HMGB1 Protein / physiology
  • 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
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / physiology*
  • Th1 Cells / cytology
  • Th1 Cells / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • p38 Mitogen-Activated Protein Kinases / physiology


  • Growth Inhibitors
  • HMGB1 Protein
  • Immune Sera
  • NF-kappa B
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Interleukin-12
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases