The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/1/225/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 2, January 17, 2000 225-238

Original Article

Neonatal Tumor Necrosis Factor {alpha} Promotes Diabetes in Nonobese Diabetic Mice by Cd154-Independent Antigen Presentation to Cd8+ T Cells

E. Allison Greena, F. Susan Wonga, Koji Eshimaa, Conchi Moraa, and Richard A. Flavella,b

a Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520
b Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520
Section of Immunobiology, Yale University School of Medicine, Howard Hughes Medical Institute, 310 Cedar St., FMB 412, P.O. Box 208011, New Haven, CT 06520-8011.203-785-7561203-785-7024

fran.manzo{at}yale.edu

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.

Key Words: TNF-{alpha} • CD154 • diabetes • NOD mice • CD8+ cells

Abbreviations used in this paper: CIITA, MHC class II–transactivating; DCs, dendritic cells; GAD, glutamic acid decarboxylase; KLH, keyhole limpet hemagglutinin; NOD, nonobese diabetic.

© 2000 The Rockefeller University Press


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