Cellular FLICE-inhibitory protein is required for T cell survival and cycling

J Exp Med. 2005 Aug 1;202(3):405-13. doi: 10.1084/jem.20050118. Epub 2005 Jul 25.

Abstract

Fas-associated death domain (FADD) and caspase-8 are key signal transducers for death receptor-induced apoptosis, whereas cellular FLICE-inhibitory protein (cFLIP) antagonizes this process. Interestingly, FADD and caspase-8 also play a role in T cell development and T cell receptor (TCR)-mediated proliferative responses. To investigate the underlying mechanism, we generated cFLIP-deficient T cells by reconstituting Rag-/- blastocysts with cFLIP-deficient embryonic stem cells. These Rag chimeric mutant mice (rcFLIP-/-) had severely reduced numbers of T cells in the thymus, lymph nodes, and spleen, although mature T lymphocytes did develop. Similar to FADD- or caspase-8-deficient cells, rcFLIP-/- T cells were impaired in proliferation in response to TCR stimulation. Further investigation revealed that cFLIP is required for T cell survival, as well as T cell cycling in response to TCR stimulation. Interestingly, some signaling pathways from the TCR complex appeared competent, as CD3 plus CD28 cross-linking was capable of activating the ERK pathway in rcFLIP-/- T cells. We demonstrate an essential role for cFLIP in T cell function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CD28 Antigens / metabolism
  • CD3 Complex / metabolism
  • Caspase 8
  • Caspases / metabolism
  • Cell Proliferation
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fas-Associated Death Domain Protein
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mice, Knockout
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CD28 Antigens
  • CD3 Complex
  • Cflar protein, mouse
  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Antigen, T-Cell
  • Extracellular Signal-Regulated MAP Kinases
  • Casp8 protein, mouse
  • Caspase 8
  • Caspases