Molecular identification of a danger signal that alerts the immune system to dying cells

Nature. 2003 Oct 2;425(6957):516-21. doi: 10.1038/nature01991. Epub 2003 Sep 7.


In infections, microbial components provide signals that alert the immune system to danger and promote the generation of immunity. In the absence of such signals, there is often no immune response or tolerance may develop. This has led to the concept that the immune system responds only to antigens perceived to be associated with a dangerous situation such as infection. Danger signals are thought to act by stimulating dendritic cells to mature so that they can present foreign antigens and stimulate T lymphocytes. Dying mammalian cells have also been found to release danger signals of unknown identity. Here we show that uric acid is a principal endogenous danger signal released from injured cells. Uric acid stimulates dendritic cell maturation and, when co-injected with antigen in vivo, significantly enhances the generation of responses from CD8+ T cells. Eliminating uric acid in vivo inhibits the immune response to antigens associated with injured cells, but not to antigens presented by activated dendritic cells. Our findings provide a molecular link between cell injury and immunity and have important implications for vaccines, autoimmunity and inflammation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Adjuvants, Immunologic / isolation & purification
  • Adjuvants, Immunologic / metabolism
  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Biological Factors / isolation & purification
  • Biological Factors / metabolism
  • Biological Factors / pharmacology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Death / immunology
  • Cell Differentiation / drug effects
  • Cells / immunology*
  • Cells / pathology*
  • Cytosol / chemistry
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Immune System / cytology
  • Immune System / drug effects*
  • Immune System / immunology*
  • Mice
  • Molecular Weight
  • Uric Acid / isolation & purification
  • Uric Acid / metabolism
  • Uric Acid / pharmacology*


  • Adjuvants, Immunologic
  • Biological Factors
  • Uric Acid