c-maf promotes T helper cell type 2 (Th2) and attenuates Th1 differentiation by both interleukin 4-dependent and -independent mechanisms.
The c-maf protooncogene is a T helper cell type 2 (Th2)-specific transcription factor that activates the interleukin (IL)-4 promoter in vitro. Although it has been postulated that c-maf directs the Th2-specific expression of the IL-4 gene in vivo, direct evidence that c-maf functions during the differentiation of normal, primary T cells is lacking. We now demonstrate that overexpression of c-maf in vivo skews the Th immune response along a Th2 pathway, as evidenced by increased production of Th2 cytokines and the IL-4-dependent immunoglobulins, IgG1 and IgE. The overproduction of IgGl and IgE in the CD4 promoter/c-maf transgenic mice was IL-4 dependent since this was not observed in c-maf transgenic mice bred onto an IL-4-deficient background. Ectopic expression of c-maf in mature Th1 cells did not confer on them the ability to produce IL-4, but did decrease the production of IFN-gamma. The attenuation of Th1 differentiation by c-maf overexpression occurred by a mechanism that was independent of IL-4 and other Th2 cytokines, and could be overcome by IL-12. These studies demonstrate that c-maf promotes Th2 differentiation by IL-4-dependent mechanisms and attenuates Th1 differentiation by Th2 cytokine-independent mechanisms.
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Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
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Glimcher
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D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000276:immunology; D007136:Immunoglobulins / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051257:Proto-Oncogene Proteins c-maf; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics
D004268:DNA-Binding Proteins; D007136:Immunoglobulins; C495608:Maf protein, mouse; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D015534:Trans-Activators; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma