Abstract
Neonatal islet-specific expression of tumor necrosis factor (TNF)-alpha in nonobese diabetic mice promotes diabetes by provoking islet-infiltrating antigen-presenting cells to present islet peptides to autoreactive T cells. Here we show that TNF-alpha promotes autoaggression of both effector CD4(+) and CD8(+) T cells. Whereas CD8(+) T cells are critical for diabetes progression, CD4(+) T cells play a lesser role. TNF-alpha-mediated diabetes development was not dependent on CD154-CD40 signals or activated CD4(+) T cells. Instead, it appears that TNF-alpha can promote cross-presentation of islet antigen to CD8(+) T cells using a unique CD40-CD154-independent pathway. These data provide new insights into the mechanisms by which inflammatory stimuli can bypass CD154-CD40 immune regulatory signals and cause activation of autoreactive T cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Animals, Newborn
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Antigen Presentation / immunology*
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Antigen-Presenting Cells / immunology
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CD4-Positive T-Lymphocytes / immunology
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CD40 Ligand
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CD8-Positive T-Lymphocytes / immunology*
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Diabetes Mellitus, Type 1 / immunology*
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Diabetes Mellitus, Type 1 / physiopathology
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Female
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Histocompatibility Antigens Class II / immunology
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Humans
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Infant, Newborn
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology*
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Mice
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Mice, Inbred NOD
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Mice, Knockout
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Mice, Transgenic
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Nuclear Proteins*
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Signal Transduction
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Trans-Activators / genetics
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Trans-Activators / immunology
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology*
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beta 2-Microglobulin / genetics
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beta 2-Microglobulin / immunology
Substances
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Histocompatibility Antigens Class II
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MHC class II transactivator protein
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Membrane Glycoproteins
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Nuclear Proteins
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Trans-Activators
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Tumor Necrosis Factor-alpha
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beta 2-Microglobulin
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CD40 Ligand