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-κB-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-FLIPL) specifically in T cells using the CD2 promoter (TgFLIPL). TgFLIPL 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, TgFLIPL 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 TgFLIPL 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-FLIPL 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.

A network-based analysis of allergen-challenged CD4+ T cells from patients with allergic rhinitis

“…It should also be noted that DNA microarray analysis had previously shown increased expression of proapoptotic genes like TNF and FAS, both of which have been described in allergic disease. 2,3,5 These findings support the hypothesis that Th2 proliferation can be seen as a net effect of multiple interacting genes, with TNFRSF4 and other genes of the TNF superfamily playing important roles.…”

“…This is in agreement with previous data analyses that appear to associate Th2 proliferation with altered regulation of apoptosis. [2][3][4][5][6] Lymphocyte death was associated with several genes of the TNF ligand and receptor superfamilies, most notably TNF, FAS, TNFRSF4, TNFRSF25, TNFRSF1B and TNFS7. These genes are involved in regulating T-cell apoptosis and proliferation.…”

“…[1][2][3][4][5][6][7] Supernatants from 11 patients and five controls were studied. In supernatants from patients, IL-5 was significantly higher in supernatants from allergen-challenged PBMC, 100 (0-500) vs 0 (0-0), Po0.01, as was IL-13, 13 (0-270) vs 0 (0-0), Po0.05.…”

“…The differentiation of Th cells is determined by a complex interplay between multiple factors such as antigen type and dose, dendritic cells, the T-cell receptor, co-stimulatory signals and the cytokine microenvironment as well as apoptotic regulators. [1][2][3][4][5][6][7] DNA microarray studies have described hundreds of differentially expressed genes in CD4 þ T cells stimulated by cytokines, 8,9 taken from transgenic mice, 10 or from peripheral blood of patients with atopic dermatitis. 11 These findings indicate that the proliferation of Th2 cells depends on multiple, interacting genes.…”

TNFRI is a positive T‐cell costimulatory molecule important for the timing of cytokine responses

“…23 Other, indirect evidence supporting a role for TNFRI in T cells comes from functional studies of a downstream-inducible protein, c-FLIP L , that is critically required for T-cell proliferation, survival and cycling in response to TCR stimulation in vitro 24,25 and for effector T-cell development in in vivo models. [26][27][28] In this study, we investigated whether TNFRI can function as a costimulatory molecule during T-cell activation. Using CD3 + -enriched…”