Fas-associated death domain (FADD) is a negative regulator of T-cell receptor-mediated necroptosis

Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13034-9. doi: 10.1073/pnas.1005997107. Epub 2010 Jul 6.


Cell death is an important mechanism to limit uncontrolled T-cell expansion during immune responses. Given the role of death-receptor adapter protein Fas-associated death domain (FADD) in apoptosis, it is intriguing that T-cell receptor (TCR)-induced proliferation is blocked in FADD-defective T cells. Necroptosis is an alternate form of death that can be induced by death receptors and is linked to autophagy. It requires the death domain-containing kinase RIP1 and, in certain instances, RIP3. FADD and its apoptotic partner, Caspase-8, have also been implicated in necroptosis. To accurately assess the role of FADD in mature T-cell proliferation and death, we generated a conditional T-cell-specific FADD knockout mouse strain. The T cells of these mice develop normally, but lack FADD at the mature stage. FADD-deficient T cells respond poorly to TCR triggering, exhibit slow cell cycle entry, and fail to expand over time. We find that programmed necrosis occurs during the late stage of normal T-cell proliferation and that this process is greatly amplified in FADD-deficient T cells. Inhibition of necroptosis using an inhibitor of RIP1 kinase activity rescues the FADD knockout proliferative defect. However, TCR-induced necroptosis did not appear to require autophagy or involve RIP3. Consistent with their defective CD8 T-cell response, these mice succumb to Toxoplasma gondii infection more readily than wild-type mice. We conclude that FADD constitutes a mechanism to keep TCR-induced programmed necrotic signaling in check during early phases of T-cell clonal expansion.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / immunology*
  • Autophagy
  • Caspase 8 / metabolism
  • Cell Cycle
  • Cell Proliferation
  • Disease Susceptibility
  • Fas-Associated Death Domain Protein / deficiency
  • Fas-Associated Death Domain Protein / metabolism*
  • Mice
  • Necrosis / immunology*
  • Phenotype
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction
  • Survival Analysis
  • T-Lymphocytes / cytology
  • T-Lymphocytes / enzymology
  • Toxoplasma / immunology
  • Toxoplasmosis / immunology
  • Toxoplasmosis / parasitology


  • Fas-Associated Death Domain Protein
  • Receptors, Antigen, T-Cell
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Ripk3 protein, mouse
  • Caspase 8