title: Cellular FLIP (long isoform) overexpression in T cells drives Th2 effector responses and promotes immunoregulation in experimental autoimmune encephalomyelitis.
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.
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, National Center for Scientific Research Demokritos, Athens, Greece.
authors.forename: Vivian
authors.initials: V
authors.lastname: Tseveleki
authors.forename: Jan
authors.initials: J
authors.lastname: Bauer
authors.forename: Era
authors.initials: E
authors.lastname: Taoufik
authors.forename: Chengmai
authors.initials: C
authors.lastname: Ruan
authors.forename: Leondios
authors.initials: L
authors.lastname: Leondiadis
authors.forename: Sylva
authors.initials: S
authors.lastname: Haralambous
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.forename: Lesley
authors.initials: L
authors.lastname: Probert
mesh_terms: D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001323:Autoantibodies / Q000096:biosynthesis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017252:CD3 Complex / Q000276:immunology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D019014:fas Receptor / Q000502:physiology
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017252:CD3 Complex; C506386:CFLAR protein, human; C506387:Cflar protein, mouse; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D020033:Protein Isoforms; D019014:fas Receptor; C445081:myelin oligodendrocyte glycoprotein (35-55)