Abstract
Cellular FLIP (c-FLIP) is an endogenous inhibitor of death receptor-induced apoptosis through the caspase 8 pathway. It is an NF-kappaB-inducible protein thought to promote the survival of T cells upon activation, and its down-regulation has been implicated in activation-induced cell death. We have generated transgenic mice overexpressing human c-FLIP long form (c-FLIP(L)) specifically in T cells using the CD2 promoter (TgFLIP(L)). TgFLIP(L) mice exhibit increased IgG1 production upon stimulation by a T cell-dependent Ag and a markedly enhanced contact hypersensitivity response to allergen. In addition to showing augmented Th2-type responses, TgFLIP(L) mice are resistant to the development of myelin oligodendrocyte glycoprotein 35-55 peptide-induced experimental autoimmune encephalomyelitis, a Th1-driven autoimmune disease. In vitro analyses revealed that T cells of TgFLIP(L) mice proliferate normally, but produce higher levels of IL-2 and show preferential maturation of Th2 cytokine-producing cells in response to antigenic stimulation. After adoptive transfer, these (Th2) cells protected wild-type recipient mice from experimental autoimmune encephalomyelitis induction. Our results show that the constitutive overexpression of c-FLIP(L) in T cells is sufficient to drive Th2 polarization of effector T cell responses and indicate that it might function as a key regulator of Th cell differentiation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / biosynthesis
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Adjuvants, Immunologic / genetics
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Adjuvants, Immunologic / physiology*
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Adoptive Transfer
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Animals
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Antibodies, Monoclonal / pharmacology
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Autoantibodies / biosynthesis
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CD3 Complex / immunology
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Cell Death / genetics
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Cell Death / immunology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Dermatitis, Contact / immunology
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / prevention & control
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Glycoproteins / immunology
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Humans
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Immunity, Innate
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism*
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Intracellular Signaling Peptides and Proteins / physiology
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Lymphocyte Activation
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Mice
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Mice, Inbred C57BL
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Mice, Inbred CBA
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Mice, Transgenic
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments / immunology
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Protein Isoforms / biosynthesis
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Protein Isoforms / genetics
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Protein Isoforms / physiology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism*
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Th2 Cells / cytology
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Th2 Cells / immunology*
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Th2 Cells / metabolism*
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Th2 Cells / transplantation
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fas Receptor / physiology
Substances
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Adjuvants, Immunologic
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Antibodies, Monoclonal
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Autoantibodies
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CD3 Complex
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CFLAR protein, human
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Cflar protein, mouse
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Glycoproteins
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Intracellular Signaling Peptides and Proteins
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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Protein Isoforms
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fas Receptor
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myelin oligodendrocyte glycoprotein (35-55)