Abstract
Bcl-3 is an atypical member of the IκB family that modulates transcription in the nucleus via association with p50 (NF-κB1) or p52 (NF-κB2) homodimers. Despite evidence attesting to the overall physiologic importance of Bcl-3, little is known about its cell-specific functions or mechanisms. Here we demonstrate a T-cell-intrinsic function of Bcl-3 in autoimmunity. Bcl-3-deficient T cells failed to induce disease in T cell transfer-induced colitis and experimental autoimmune encephalomyelitis. The protection against disease correlated with a decrease in Th1 cells that produced the cytokines IFN-γ and GM-CSF and an increase in Th17 cells. Although differentiation into Th1 cells was not impaired in the absence of Bcl-3, differentiated Th1 cells converted to less-pathogenic Th17-like cells, in part via mechanisms involving expression of the RORγt transcription factor. Thus, Bcl-3 constrained Th1 cell plasticity and promoted pathogenicity by blocking conversion to Th17-like cells, revealing a unique type of regulation that shapes adaptive immunity.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Autoimmunity / immunology*
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B-Cell Lymphoma 3 Protein
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Cell Differentiation / immunology
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Colitis / immunology
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis*
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Homeodomain Proteins / genetics
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Interferon-gamma / biosynthesis*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B p50 Subunit / immunology
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NF-kappa B p52 Subunit / immunology
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Nuclear Receptor Subfamily 1, Group F, Member 3 / biosynthesis
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Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / immunology*
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Th1 Cells / immunology*
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Th1 Cells / transplantation
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Th17 Cells / immunology*
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Transcription Factors / genetics
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Transcription Factors / immunology*
Substances
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B-Cell Lymphoma 3 Protein
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Bcl3 protein, mouse
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Homeodomain Proteins
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NF-kappa B p50 Subunit
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NF-kappa B p52 Subunit
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Proto-Oncogene Proteins
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Transcription Factors
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RAG-1 protein
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Interferon-gamma
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Granulocyte-Macrophage Colony-Stimulating Factor