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School of Pharmacy, University of Southern California, Los Angeles, CA 90033
To investigate how CD8+ T cells interact with ß cells
and local inflammatory cells in islets, we have isolated
CD8+ T cell clones from nonobese diabetic (NOD) spleen that
recognize and destroy both islets and the NOD insulinoma cell line
NIT-1. The clones destroyed NOD islets with pre-existing inflammation
better than islets without signs of inflammation. Islets from NOD-scid
mice were destroyed only poorly, but that could be improved by adding
IL-7 to the assay. Anti-IFN-
Abs inhibited destruction of
infiltrated islets. Single islets were effective stimulators of IFN-
production by cloned CD8+ T cells, which varied >50-fold
depending on the degree of islet infiltration. This effect of the islet
mononuclear infiltrate could be mimicked by adding spleen cells to
NIT-1 cells, which augmented IFN- production above the level
stimulated by NIT-1 cells alone. The enhancing effect of spleen cells
could be attributed to their macrophage subpopulation and was not MHC
restricted, although recognition of islet Ag by cloned CD8+
T cells and subsequent islet destruction was restricted to islets
expressing H-2Db molecules. An inhibitor of inducible NO
synthase inhibited destruction of inflamed islets by cloned
CD8+ T cells. We propose that macrophages in inflamed
islets provide a form of bystander costimulation of ß cell-specific
CD8+ T cells. CD8+ T cells respond to Ag and
costimulation by producing IFN- that activates macrophages.
Activated macrophages facilitate islet destruction by CD8+
T cells through a NO synthesis-dependent
pathway.
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