Original Article

Neonatal Tumor Necrosis Factor Promotes Diabetes in Nonobese Diabetic Mice by CD154-independent Antigen Presentation to CD8⁺ T Cells

Correspondence to: Richard A. Flavell, Section of Immunobiology, Yale University School of Medicine, Howard Hughes Medical Institute, 310 Cedar St., FMB 412, P.O. Box 208011, New Haven, CT 06520-8011. Tel:203-785-7024 Fax:203-785-7561 E-mail:fran.manzo{at}yale.edu.

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

Key Words: TNF-, CD154, diabetes, NOD mice, CD8⁺ cells

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