Abstract
Survival of antigen-experienced T cells is essential for the generation of adaptive immune responses. Here, we show that the genetic and antibody-mediated inactivation of CD152 (cytotoxic T lymphocyte antigen 4) in T helper (Th) effector cells reduced the frequency of nonapoptotic cells in a completely Fas/Fas ligand (FasL)-dependent manner. CD152 cross-linking together with stimulation of CD3 and CD28 on activated Th2 cells prevented activation-induced cell death (AICD) as a result of reduced Fas and FasL expression. Apoptosis protection conferred by CD152 correlated with the up-regulation of Bcl-2 and was mediated by phosphatidylinositol 3 kinase, which prevented FasL expression through the inhibitory phosphorylation of Forkhead transcription factor FKHRL1. We show that signals induced by CD152 act directly on activated T lymphocytes and, due to its differential surface expression on activated Th1 and Th2 cells, induce resistance to AICD mainly in Th2 cells.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD
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Antigens, Differentiation / metabolism*
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Apoptosis / immunology*
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Apoptosis / physiology
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CTLA-4 Antigen
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Cell Cycle / physiology
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DNA Primers
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DNA-Binding Proteins / metabolism
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Fas Ligand Protein
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Fluorescent Antibody Technique / methods
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Gene Expression Regulation*
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Genes, bcl-2 / physiology
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Genotype
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Image Cytometry
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Immunoblotting
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Transgenic
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Microspheres
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Phosphatidylinositol 3-Kinases / metabolism*
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Polymerase Chain Reaction
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Signal Transduction / physiology*
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th1 Cells / physiology*
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Th2 Cells / immunology
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Th2 Cells / metabolism
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Th2 Cells / physiology*
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Transcription Factors / metabolism
Substances
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Antigens, CD
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Antigens, Differentiation
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CTLA-4 Antigen
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Ctla4 protein, mouse
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DNA Primers
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DNA-Binding Proteins
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Fas Ligand Protein
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Fasl protein, mouse
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Membrane Glycoproteins
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Transcription Factors
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Phosphatidylinositol 3-Kinases