Neonatal islet-specific expression of tumor necrosis factor (TNF)-α 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-α 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-α–mediated diabetes development was not dependent on CD154–CD40 signals or activated CD4⁺ T cells. Instead, it appears that TNF-α 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.