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Title

A mouse CD8 T cell-mediated acute autoimmune diabetes independent of the perforin and Fas cytotoxic pathways: possible role of membrane TNF

Authors
Harlan, D. M.
Published in Proceedings of the National Academy of Sciences of the United States of America. 2000, vol. 97, no. 1, p. 279-284
Abstract Double transgenic mice [rat insulin promoter (RIP)-tumor necrosis factor (TNF) and RIP-CD80] whose pancreatic beta cells release TNF and bear CD80 all develop an acute early (6 wk) and lethal diabetes mediated by CD8 T cells. The first ultrastructural changes observed in beta cells, so far unreported, are focal lesions of endoplasmic reticulum swelling at the points of contact with islet-infiltrating lymphoblasts, followed by cytoplasmic, but not nuclear, apoptosis. Such double transgenic mice were made defective in either the perforin, Fas, or TNF pathways. Remarkably, diabetes was found to be totally independent of perforin and Fas. Mice lacking TNF receptor (TNFR) II had no or late diabetes, but only a minority had severe insulitis. Mice lacking the TNF-lymphotoxin (LTalpha) locus (whose sole source of TNF are the beta cells) all had insulitis comparable to that of nondefective mice, but no diabetes or a retarded and milder form, with lesions suggesting different mechanisms of injury. Because both TNFR II and TNF-LTalpha mutations have complex effects on the immune system, these data do not formally incriminate membrane TNF as the major T cell mediator of this acute autoimmune diabetes; nevertheless, in the absence of involvement of the perforin or Fas cytotoxic pathways, membrane TNF appears to be the likeliest candidate.
Keywords AnimalsAntigens, CD/metabolismAntigens, CD80/genetics/immunologyAntigens, CD95/ genetics/immunologyApoptosis/genetics/immunologyAutoimmunity/ immunologyCD8-Positive T-Lymphocytes/ immunologyDiabetes Mellitus/ genetics/immunologyDisease Models, AnimalFluorescent Antibody TechniqueInsulin/geneticsIslets of Langerhans/immunology/pathologyMembrane Glycoproteins/ genetics/immunologyMiceMice, KnockoutMice, TransgenicMicroscopy, ElectronPancreas/pathologyPerforinPore Forming Cytotoxic ProteinsPromoter Regions, GeneticReceptors, Tumor Necrosis Factor/geneticsReceptors, Tumor Necrosis Factor, Type IISignal Transduction/geneticsTumor Necrosis Factor-alpha/ genetics
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PMID: 10618409
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HERRERA, Pedro Luis, HARLAN, D. M., VASSALLI, Pierre. A mouse CD8 T cell-mediated acute autoimmune diabetes independent of the perforin and Fas cytotoxic pathways: possible role of membrane TNF. In: Proceedings of the National Academy of Sciences of the United States of America, 2000, vol. 97, n° 1, p. 279-284. doi: 10.1073/pnas.97.1.279 https://archive-ouverte.unige.ch/unige:8807

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Deposited on : 2010-07-12

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