Transcription mediated by NFAT is highly inducible in effector CD4+ T helper 2 (Th2) cells but not in Th1 cells.
TLDR
Rec reporter transgenic mice are used to show that DNA binding and transcriptional activities of NFAT are transiently induced during the differentiation of pTh cells into either eTh1 or eTh2 cells to mediate the expression of IL-2 as a common growth factor in both pathways, suggesting that activated NFAT is involved in the effector function of eTh 2 cells.Abstract:
Transcriptional factors of the NFAT family play an important role in regulating the expression of several cytokine genes during the immune response, such as the genes for interleukin 2 (IL-2) and IL-4, among others. Upon antigen stimulation, precursor CD4+ T helper (pTh) cells proliferate and differentiate into two populations of effector cells (eTh1 and eTh2), each one expressing a specific pattern of cytokines that distinguishes them from their precursors. eTh2 cells are the major source of IL-4, while gamma interferon is produced by eTh1 cells. Here we have used reporter transgenic mice to show that DNA binding and transcriptional activities of NFAT are transiently induced during the differentiation of pTh cells into either eTh1 or eTh2 cells to mediate the expression of IL-2 as a common growth factor in both pathways. However, although NFAT DNA binding is similarly induced in both eTh1 and eTh2 cells upon antigen stimulation, only the NFAT complexes present in eTh2 cells are able to mediate high-level transcription, and relatively little NFAT transcriptional activity was induced in eTh1 cells. In contrast to activated pTh cells, neither eTh1 nor eTh2 cells produced significant IL-2 upon stimulation, but the high levels of NFAT transcriptional activities directly correlate with the IL-4 production induced in response to antigen stimulation in eTh2 cells. These data suggest that activated NFAT is involved in the effector function of eTh2 cells and that the failure of eTh1 cells to produce IL-4 in response to an antigen is due, at least partially, to a failure to induce high-level transcription of the IL-4 gene by NFAT. Regulation of NFAT could be therefore a critical element in the polarization to eTh1 or eTh2.read more
Citations
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The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells
TL;DR: In transgenic mice, elevated GATA-3 in CD4 T cells caused Th2 cytokine gene expression in developing Th1 cells, indicating that Gata-3 is necessary and sufficient for Th2inflammatory gene expression.
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Cytokines Induce the Development of Functionally Heterogeneous T Helper Cell Subsets
TL;DR: I would like to thank Bob Coffman, Thierry von der Weid, Nancy Hosken, Amy Beebe, Steve Hurst, and Douglas Robinson for useful suggestions and discussion and Lewis Lanier for critical reviewing of the mansucript.
Journal ArticleDOI
Signaling and Transcription in T Helper Development
Kenneth M. Murphy,Wenjun Ouyang,J. David Farrar,Jianfei Yang,Sheila Ranganath,Hélène Asnagli,Maryam Afkarian,Theresa L. Murphy +7 more
TL;DR: What has emerged is a richly detailed tapestry of signaling and transcription, controlling an important T cell developmental switch, particularly by the strongly polarizing cytokines IL-12 and IL-4.
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The caspase-8 inhibitor FLIP promotes activation of NF-κB and Erk signaling pathways
Takao Kataoka,Ralph C. Budd,Ralph C. Budd,Nils Holler,Margot Thome,Fabio Martinon,Martin Irmler,Kim Burns,Michael Hahne,Norman J. Kennedy,M. Kovacsovics,J. Tschopp +11 more
TL;DR: Evidence is provided that FLIP is not simply an inhibitor of death-receptor-induced apoptosis but that it also mediates the activation of NF-kappaB and Erk by virtue of its capacity to recruit adaptor proteins involved in these signaling pathways.
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Interferon‐γ expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway
Mercedes Rincon,Hervé Enslen,Joel Raingeaud,Joel Raingeaud,Michael I. Recht,Tyler Zapton,Michael S‐S. Su,Laurie A. Penix,Roger J. Davis,Richard A. Flavell +9 more
TL;DR: It is shown that pyridinyl imidazole compounds (specific inhibitors of p38 MAP kinase) block the production of interferon‐γ (IFNγ) by Th1 cells without affecting IL‐4 production by Th2 cells, and that inhibition of p 38 MAP kinases represents a possible site of therapeutic intervention in diseases where a predominant Th1 immune response leads to a pathological outcome.
References
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