Neonatal Tumor Necrosis Factor a Promotes Diabetes in Nonobese Diabetic Mice by CD154-independent Antigen

Neonatal islet-specific expression of tumor necrosis factor (TNF)a 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 TNFa promotes autoaggression of both effector CD4 1 and CD8 1 T cells. Whereas CD8 1 T cells are critical for diabetes progression, CD4 1 T cells play a lesser role. TNFa –mediated diabetes development was not dependent on CD154– CD40 signals or activated CD4 1 T cells. Instead, it appears that TNFa can promote cross-presentation of islet antigen to CD8 1 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.