Abstract
Sle1a.1 is part of the Sle1 susceptibility locus, which has the strongest association with lupus nephritis in the NZM2410 mouse model. In this study, we show that Sle1a.1 results in the production of activated and autoreactive CD4(+) T cells. Additionally, Sle1a.1 expression reduces the peripheral regulatory T cell pool, as well as induces a defective response of CD4(+) T cells to the retinoic acid expansion of TGF-β-induced regulatory T cells. At the molecular level, Sle1a.1 corresponds to an increased expression of a novel splice isoform of Pbx1, Pbx1-d. Pbx1-d overexpression is sufficient to induce an activated/inflammatory phenotype in Jurkat T cells and to decrease their apoptotic response to retinoic acid. PBX1-d is expressed more frequently in the CD4(+) T cells from lupus patients than from healthy controls, and its presence correlates with an increased central memory T cell population. These findings indicate that Pbx1 is a novel lupus susceptibility gene that regulates T cell activation and tolerance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Female
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Genetic Predisposition to Disease*
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Homeodomain Proteins / biosynthesis
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Homeodomain Proteins / genetics
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Homeodomain Proteins / physiology*
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Humans
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Immune Tolerance / genetics
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Immunologic Memory / genetics
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Jurkat Cells
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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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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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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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Middle Aged
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Molecular Sequence Data
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Pre-B-Cell Leukemia Transcription Factor 1
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Protein Isoforms / genetics
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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RNA Splicing / immunology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / pathology
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Transcription Factors / physiology*
Substances
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DNA-Binding Proteins
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Homeodomain Proteins
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Pbx1 protein, mouse
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Pre-B-Cell Leukemia Transcription Factor 1
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Protein Isoforms
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Proto-Oncogene Proteins
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Transcription Factors
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PBX1 protein, human
Associated data
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GENBANK/HM369110
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GEO/GSE22313
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GEO/GSE22799