myelin-oligodendrocyte-glycoprotein-(35-55) and Dermatitis--Contact

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.

Topics: Adjuvants, Immunologic; Adoptive Transfer; Animals; Antibodies, Monoclonal; Autoantibodies; CASP8 and FADD-Like Apoptosis Regulating Protein; CD3 Complex; Cell Death; Cell Differentiation; Dermatitis, Contact; Encephalomyelitis, Autoimmune, Experimental; fas Receptor; Glycoproteins; Humans; Immunity, Innate; Intracellular Signaling Peptides and Proteins; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Protein Isoforms; T-Lymphocyte Subsets; Th2 Cells