Abstract
Activation-induced cell death (AICD) of T cells is one of the major mechanisms of peripheral tolerance. The regulation of AICD by IL-4 is poorly understood. In this study, we report that AICD in IL-4-deficient T cells is significantly reduced compared with that in wild-type T cells. This impaired AICD correlates with the failure to induce degradation of cellular FLIP. IL-4-mediated enhancement of AICD and cellular FLIP degradation requires a Janus kinase/STAT-6 signaling pathway. Unexpectedly, these effects of IL-4 could be blocked by a neutralizing anti-IL-2 Ab, and addition of rIL-2 could completely restore the defective AICD in IL-4-deficient T cells. Furthermore, IL-4 regulates the T cell thresholds for IL-2 signaling during AICD. These data suggest that IL-4 promotes AICD via an IL-2-dependent mechanism.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adjuvants, Immunologic / deficiency
-
Adjuvants, Immunologic / genetics
-
Adjuvants, Immunologic / physiology*
-
Animals
-
Apoptosis / genetics
-
Apoptosis / immunology*
-
CASP8 and FADD-Like Apoptosis Regulating Protein
-
Carrier Proteins / metabolism
-
Cells, Cultured
-
Drug Synergism
-
Fas Ligand Protein
-
Interleukin-2 / physiology*
-
Interleukin-4 / deficiency
-
Interleukin-4 / genetics
-
Interleukin-4 / physiology*
-
Intracellular Signaling Peptides and Proteins*
-
Ligands
-
Lymphocyte Activation* / genetics
-
Membrane Glycoproteins / biosynthesis
-
Mice
-
Mice, Inbred BALB C
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, Transgenic
-
Proto-Oncogene Proteins c-bcl-2 / biosynthesis
-
Receptors, Antigen, T-Cell / physiology
-
STAT6 Transcription Factor
-
Signal Transduction / immunology
-
T-Lymphocyte Subsets / cytology*
-
T-Lymphocyte Subsets / immunology*
-
T-Lymphocyte Subsets / metabolism
-
Trans-Activators / deficiency
-
Trans-Activators / genetics
-
Trans-Activators / physiology
-
Up-Regulation / immunology
-
fas Receptor / metabolism
Substances
-
Adjuvants, Immunologic
-
CASP8 and FADD-Like Apoptosis Regulating Protein
-
Carrier Proteins
-
Cflar protein, mouse
-
Fas Ligand Protein
-
Fasl protein, mouse
-
Interleukin-2
-
Intracellular Signaling Peptides and Proteins
-
Ligands
-
Membrane Glycoproteins
-
Proto-Oncogene Proteins c-bcl-2
-
Receptors, Antigen, T-Cell
-
STAT6 Transcription Factor
-
Stat6 protein, mouse
-
Trans-Activators
-
fas Receptor
-
Interleukin-4