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*
Ontario Cancer Institute/Amgen Institute, Toronto, Ontario, Canada; and
Department of Pathology, University of Zürich, Zürich, Switzerland
Autoimmune diabetes is characterized by a chronic progressive
inflammatory autoimmune reaction that ultimately causes the selective
elimination of pancreatic ß cells. To address the question of whether
the cell death-inducing cytokines TNF and lymphotoxin 
are involved
in this process, we generated nonobese diabetic (NOD) mice that are
deficient for TNF receptor 1 (TNFR1 or TNFRp55). Insulitis developed in
these mice similarly to that in normal control NOD mice, but
progression to diabetes was completely abrogated. Since this was
probably due to the complex immunomodulatory effects of TNF and
lymphotoxin signaled via TNFR1 on lymphohemopoietic cells, adoptive
transfer experiments with spleen cells from diabetic NOD mice were
conducted. It was found that the absence of TNFR1 in recipients delayed
diabetes induced by normal control and precluded diabetes induced by
perforin-deficient spleen cells. In a CD8+ T cell-mediated
model of diabetes, however, diabetes induced by adoptive transfer of
TCR transgenic lymphocytic choriomeningitis virus glycoprotein-specific
CD8+ T cells was not delayed by the absence of TNFR1 in
recipient mice. Together with the described expression patterns of
perforin and TNF in the mononuclear islet infiltrates of NOD mice,
these results indicate that two diabetogenic effector mechanisms are
delivered by distinct cell populations: CD8+ T cells lyse
ß cells via perforin-dependent cytotoxicity, whereas CD4+
T cells, macrophages, and dendritic cells contribute to diabetes
development via TNFR1-dependent ß cell
toxicity.
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