Abstract
CD4+ T cells with a block in the NF-kappaB signaling pathway exhibit decreases in Th1 responses and diminished nuclear levels of multiple transactivating NF-kappaB/Rel/IkappaB proteins. To determine the lineage-intrinsic contributions of these transactivators to Th differentiation, T cells from mice deficient in specific subunits were cultured in exogenous cytokines promoting either Th1 or Th2 differentiation. RelB-deficient cells exhibited dramatic defects in Th1 differentiation and IFN-gamma production, whereas no consistent defect in either Th1 or Th2 responses was observed with c-Rel-deficient cells. In sharp contrast, Bcl-3-null T cells displayed no defect in IFN-gamma production, but their Th2 differentiation and IL-4, IL-5, and IL-13 production were significantly impaired. The absence of RelB led to a dramatic decrease in the expression of T-box expressed in T cells and Stat4. In contrast, Bcl-3-deficient cells exhibited decreased GATA-3, consistent with evidence that Bcl-3 can transactivate a gata3 promoter. These data indicate that Bcl-3 and RelB exert distinct and opposing effects on the expression of subset-determining transcription factors, suggesting that the characteristics of Th cell responses may be regulated by titrating the stoichiometry of transactivating NF-kappaB/Rel/IkappaB complexes in the nuclei of developing helper effector cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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B-Cell Lymphoma 3 Protein
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Cell Differentiation / immunology*
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Cells, Cultured
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DNA-Binding Proteins / physiology
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GATA3 Transcription Factor / biosynthesis
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GATA3 Transcription Factor / deficiency
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GATA3 Transcription Factor / metabolism*
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Humans
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / biosynthesis
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Jurkat Cells
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Polycomb Repressive Complex 1
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-rel / biosynthesis
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Proto-Oncogene Proteins c-rel / deficiency
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Proto-Oncogene Proteins c-rel / metabolism
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T-Box Domain Proteins
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T-Lymphocytes, Helper-Inducer / cytology
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T-Lymphocytes, Helper-Inducer / immunology*
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Th1 Cells / cytology
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Th1 Cells / metabolism*
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Th2 Cells / metabolism*
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Transcription Factors / biosynthesis
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Transcription Factors / metabolism*
Substances
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B-Cell Lymphoma 3 Protein
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BCL3 protein, human
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Bcl3 protein, mouse
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DNA-Binding Proteins
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Pcgf6 protein, mouse
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-rel
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Transcription Factors
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Interferon-gamma
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Polycomb Repressive Complex 1