Neonatal tumor necrosis factor alpha promotes diabetes in nonobese diabetic mice by CD154-independent antigen presentation to CD8(+) T cells

E A Green, F S Wong, K Eshima, C Mora, R A Flavell

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)225-38
Number of pages14
JournalJournal of Experimental Medicine
Volume191
Issue number2
Publication statusPublished - 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

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