Abstract
The transcription factor Bach2 is a susceptible gene for numerous autoimmune diseases including systemic lupus erythematosus (SLE). Bach2-/- mice can develop a lupus-like autoimmune disease. However, the exact cellular and molecular mechanisms via which Bach2 protects the hosts from developing autoimmunity remains incompletely understood. Here, we report that Bach2 ablation on T cells, but not B cells, resulted in humoral autoimmunity, and this was associated with expansion of T follicular helper (Tfh) cells and abnormal germinal centers. Bach2 was down-regulated in Tfh cells and directly suppressed by the Tfh-defining transcription factor BCL6. Mechanistically, Bach2 directly suppresses the transcription of Cxcr5 and c-Maf, two key regulators of Tfh cell differentiation. Bach2-deficient Tfh cells were skewed toward the IL-4-producing subset, which induced IgG1 and IgE isotype switching of B cells. Heterozygous Bcl6 deficiency reduced the formation of germinal center and autoantibodies, and ameliorated the pathology in Bach2-deficient mice. Our findings identify Bach2 as a crucial negative regulator of Tfh cells at steady state and prove that Bach2 controls autoimmunity in part by restraining accumulation of pathogenic Tfh cells.
Keywords:
BCL6; Bach2; IL-4; T follicular helper cells; autoimmunity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoantibodies / immunology
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Autoimmunity / genetics
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Autoimmunity / immunology*
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Basic-Leucine Zipper Transcription Factors / deficiency
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Basic-Leucine Zipper Transcription Factors / genetics
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Basic-Leucine Zipper Transcription Factors / immunology*
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cells, Cultured
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Gene Expression Profiling / methods
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Germinal Center / immunology
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Germinal Center / metabolism
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Interleukin-4 / genetics
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Interleukin-4 / immunology*
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Interleukin-4 / metabolism
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / immunology
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Lupus Erythematosus, Systemic / metabolism
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Proto-Oncogene Proteins c-maf / genetics
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Proto-Oncogene Proteins c-maf / immunology
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Proto-Oncogene Proteins c-maf / metabolism
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Receptors, CXCR5 / genetics
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Receptors, CXCR5 / immunology
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Receptors, CXCR5 / metabolism
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism
Substances
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Autoantibodies
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Bach2 protein, mouse
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Basic-Leucine Zipper Transcription Factors
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CXCR5 protein, mouse
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Proto-Oncogene Proteins c-maf
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Receptors, CXCR5
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Interleukin-4