Enzymatically active single chain caspase-8 maintains T-cell survival during clonal expansion

Cell Death Differ. 2011 Jan;18(1):90-8. doi: 10.1038/cdd.2010.69. Epub 2010 Jun 4.


The extrinsic, or death receptor, pathway integrates apoptotic signals through the protease caspase-8 (casp8). Beyond cell death regulation, non-apoptotic functions of casp8 include its essential requirement for hematopoiesis and lymphocyte clonal expansion, and tempering of autophagy in T cells. However, the mechanistic basis for the control of these disparate cellular processes remains elusive. Here, we show that casp8-deficient T-cell survival was rescued by enzymatically active, but not inactive, casp8-expressing retroviruses. The casp8 catalytic induction in proliferating T cell occurred independent of extrinsic and intrinsic apoptotic-signaling cascades and did not induce casp8 proteolytic processing. Using a biotinylated probe selectively targeting enzymatically active caspases, catalytically active full-length casp8 was found in vivo in dividing T cells. A casp8 D387A processing mutant was able to rescue casp8-deficient T-cell proliferation, validating that casp8 self-processing is not required for its non-apoptotic function(s). Finally, casp8 activity was highest in CD8(+) T cells, the most rapidly proliferating subset. These results show that the catalytically competent form of casp8 is required for rapid T-cell proliferation in response to TCR ligation, but that processing of the caspase is only necessary to promote apoptosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Apoptosis
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Cell Proliferation
  • Cell Survival
  • Fas-Associated Death Domain Protein / metabolism
  • Mice
  • Mice, Transgenic
  • Mutagenesis, Site-Directed
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / immunology


  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Receptors, Antigen, T-Cell
  • Caspase 8