Abstract
In type 1 diabetes, the breach of central and peripheral tolerance results in autoreactive T cells that destroy insulin-producing, pancreatic beta cells. In this study, we identify a critical subpopulation of dendritic cells responsible for mediating both the cross-presentation of islet Ags to CD8(+) T cells and the direct presentation of beta cell Ags to CD4(+) T cells. These cells, termed merocytic dendritic cells (mcDCs), are more numerous in the NOD mouse and, when Ag-loaded, rescue CD8(+) T cells from peripheral anergy and deletion while stimulating islet-reactive CD4(+) T cells. When purified from the pancreatic lymph nodes of overtly diabetic NOD mice, mcDCs break peripheral T cell tolerance to beta cells in vivo and induce rapid onset type 1 diabetes in the young NOD mouse. Thus, the mcDC subset appears to represent the long-sought APC responsible for breaking peripheral tolerance to beta cell Ags in vivo.
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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Animals
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Antigens / immunology*
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CD11b Antigen / immunology
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CD11b Antigen / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8 Antigens / immunology
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CD8 Antigens / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cross-Priming / immunology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / transplantation
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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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Female
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Flow Cytometry
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Immune Tolerance / immunology
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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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Interferon Type I / metabolism
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Male
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred NOD
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Mice, Inbred Strains
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Mice, Transgenic
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
Substances
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Antigens
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CD11b Antigen
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CD8 Antigens
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Interferon Type I
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Membrane Proteins
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flt3 ligand protein