Abstract
Anti-insulin autoimmunity is one of the primary forces in initiating and progressing β-cell destruction in type 1 diabetes. While insulin expression in thymic medullary epithelial cells has been shown to be essential for establishing β-cell central tolerance, the function of insulin expression in antigen-presenting cells (APCs) of hematopoietic lineage remains elusive. With a Cre-lox reporter approach, we labeled Aire-expressing cells with enhanced yellow fluorescent proteins, and found that insulin expression in the spleen was restricted predominantly to a population of Aire(+)CD11c(int)B220(+) dendritic cells (DCs). Targeted insulin deletion in APCs failed to induce anti-islet autoimmunity in B6 mice. In contrast, elevated levels of T cell infiltration into islets were observed in B6(g7) congenic mice when insulin was specifically deleted in their CD11c-expressing DCs (B6(g7)·CD11c-ΔIns mice). Thus, insulin expression in BM-derived, Aire(+) tolerogenic DCs may play an essential role to prevent the activation and expansion of insulin-reactive T cells in the periphery.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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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.
MeSH terms
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AIRE Protein
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Animals
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Autoimmunity
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Bacterial Proteins / genetics
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / pathology
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Diabetes Mellitus, Type 1 / genetics
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Diabetes Mellitus, Type 1 / immunology*
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Diabetes Mellitus, Type 1 / metabolism
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Diabetes Mellitus, Type 1 / pathology
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Epithelial Cells / immunology
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Female
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Gene Expression
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Genes, Reporter
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Insulin / genetics
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Insulin / immunology*
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Insulin / metabolism
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Insulin-Secreting Cells / immunology*
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Insulin-Secreting Cells / metabolism
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Insulin-Secreting Cells / pathology
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Luminescent Proteins / genetics
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Male
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Mice
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Mice, Transgenic
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Neutrophil Infiltration
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Peripheral Tolerance*
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Spleen / immunology
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Spleen / pathology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology
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Transcription Factors / genetics
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Transcription Factors / immunology*
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Transcription Factors / metabolism
Substances
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Bacterial Proteins
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Insulin
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Luminescent Proteins
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Transcription Factors
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yellow fluorescent protein, Bacteria