International Immunology, Vol. 12, No. 6, 851-860,
June 2000
© 2000 Japanese Society for Immunology
Regulation of TCR-induced IFN-
release from islet-reactive non-obese diabetic CD8+ T cells by prostaglandin E2 receptor signaling
School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, USA
Correspondence to: H. von Grafenstein
Prostaglandins (PG) are released during tissue injury and inflammation, and inhibit immune responses at many points. PG may be one of several factors that protect not only against injury-induced, but also spontaneous, organ-specific autoimmune disease. Here we show that the production of PGE2, normally produced at a very low rate in islets of Langerhans, is significantly increased in inflamed islets of non-obese diabetic (NOD) mice. We investigated a possible role of PGE2 in controlling TCR-dependent release of IFN-
from islet-reactive NOD CD8+ T cells. PGE2 inhibited anti-TCR antibody-triggered release of IFN- from CD8+ T cell clone 8D8 and from polyclonal cytotoxic T lymphocytes (CTL). Using receptor subtype selective agonists, we present evidence that the effect of PGE2 is mediated by EP2 and EP4 receptors, both of which are coupled to an increase in intracellular cAMP production. The cAMP analogs 8-Br-cAMP and Sp-cAMPS mimic the effect of EP2/EP4 receptor agonists, inhibiting TCR-triggered IFN- release from NOD CD8+ T cells in a dose-dependent manner. The inhibitory effect of PGE2 was largely reversed by IL-2 added at the time of culture initiation and decreased with increasing strength of stimulation through the TCR. Resting CTL were more sensitive to PGE2 than recently expanded CTL and NOD CD8+ T cells remained insensitive to PGE2 for a longer time than BALB/c cells. Our study suggests that PGE2 may be part of a regulatory network that controls local activation of T cells and may play a role in the balance between the development of islet autoimmunity or maintenance of tolerance.
Keywords: cell cell interactions, cytokine, cytotoxic T lymphocyte, diabetes, rodent
The first two authors contributed equally to this work
Transmitting editor: J.-F. Bach
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