Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation

J Immunol. 2014 Jun 15;192(12):5548-60. doi: 10.4049/jimmunol.1400122. Epub 2014 May 7.


Caspase-8, an executioner enzyme in the death receptor pathway, was shown to initiate apoptosis and suppress necroptosis. In this study, we identify a novel, cell death-independent role for caspase-8 in dendritic cells (DCs): DC-specific expression of caspase-8 prevents the onset of systemic autoimmunity. Failure to express caspase-8 has no effect on the lifespan of DCs but instead leads to an enhanced intrinsic activation and, subsequently, more mature and autoreactive lymphocytes. Uncontrolled TLR activation in a RIPK1-dependent manner is responsible for the enhanced functionality of caspase-8-deficient DCs, because deletion of the TLR-signaling mediator, MyD88, ameliorates systemic autoimmunity induced by caspase-8 deficiency. Taken together, these data demonstrate that caspase-8 functions in a cell type-specific manner and acts uniquely in DCs to maintain tolerance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • Caspase 8 / genetics
  • Caspase 8 / immunology*
  • Dendritic Cells / immunology*
  • Immune Tolerance / physiology*
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology*
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology


  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Toll-Like Receptors
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Casp8 protein, mouse
  • Caspase 8