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The Journal of Immunology, 1999, 163: 5770-5780.
Copyright © 1999 by The American Association of Immunologists

Role of Inflammatory Infiltrate in Activation and Effector Function of Cloned Islet Reactive Nonobese Diabetic CD8+ T Cells: Involvement of a Nitric Oxide-Dependent Pathway1

Tatyana Gurlo, Kenneth Kawamura and Hermann von Grafenstein2

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-{gamma} Abs inhibited destruction of infiltrated islets. Single islets were effective stimulators of IFN-{gamma} 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-{gamma} 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-{gamma} that activates macrophages. Activated macrophages facilitate islet destruction by CD8+ T cells through a NO synthesis-dependent pathway.




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