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.
Original language | English |
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Pages (from-to) | 225-38 |
Number of pages | 14 |
Journal | Journal of Experimental Medicine |
Volume | 191 |
Issue number | 2 |
Publication status | Published - 2000 |
Keywords
- Animals
- Animals, Newborn
- Antigen Presentation
- Antigen-Presenting Cells
- CD4-Positive T-Lymphocytes
- CD40 Ligand
- CD8-Positive T-Lymphocytes
- Diabetes Mellitus, Type 1
- Female
- Histocompatibility Antigens Class II
- Humans
- Infant, Newborn
- Male
- Membrane Glycoproteins
- Mice
- Mice, Inbred NOD
- Mice, Knockout
- Mice, Transgenic
- Nuclear Proteins
- Signal Transduction
- Trans-Activators
- Tumor Necrosis Factor-alpha
- beta 2-Microglobulin