Regulation of TCR-induced IFN-gamma release from islet-reactive non-obese diabetic CD8(+) T cells by prostaglandin E(2) receptor signaling.
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 PGE(2), 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 PGE(2) in controlling TCR-dependent release of IFN-gamma from islet-reactive NOD CD8(+) T cells. PGE(2) inhibited anti-TCR antibody-triggered release of IFN-gamma 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 PGE(2) is mediated by EP(2) and EP(4) 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 EP(2)/EP(4) receptor agonists, inhibiting TCR-triggered IFN-gamma release from NOD CD8(+) T cells in a dose-dependent manner. The inhibitory effect of PGE(2) 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 PGE(2) than recently expanded CTL and NOD CD8(+) T cells remained insensitive to PGE(2) for a longer time than BALB/c cells. Our study suggests that PGE(2) 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.
Ganapathy
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School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Gurlo
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T
Jarstadmarken
H O
HO
von Grafenstein
H
H
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism*; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000502:physiology*
D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D018078:Receptors, Prostaglandin E; D007371:Interferon-gamma; D000242:Cyclic AMP; D015232:Dinoprostone