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Inhibition of T Cell Apoptosis in the Aqueous Humor of Patients with Uveitis by IL-6/Soluble IL-6 Receptor trans-Signaling

S. John Curnow^2,*,, Dagmar Scheel-Toellner^*, Will Jenkinson^*, Karim Raza^*, Omar M. Durrani, Jeff M. Faint^*, Saaeha Rauz, Kaska Wloka^*,, Darrell Pilling^*, Stefan Rose-John, Christopher D. Buckley^*, Philip I. Murray and Mike Salmon^*

^* Department of Rheumatology, Medical Research Council Centre for Immune Regulation, Division of Immunity and Infection, Medical School, The University of Birmingham, and Academic Unit of Ophthalmology, Division of Immunity and Infection, The University of Birmingham, Birmingham and Midland Eye Centre, City Hospital NHS Trust, Birmingham, United Kingdom; and Department of Biochemistry, Christian Albrechts Universität zu Kiel, Kiel, Germany

A fundamental mechanism of immune privilege in the eye is the induction of T lymphocyte apoptosis. Intraocular inflammation in uveitis implies compromise of immune privilege. This study sought to determine whether apoptosis of T cells is actively inhibited in patients with uveitis and by what pathways this may occur. Apoptotic lymphocytes were found to be absent from aqueous humor (AqH) of virtually all patients with recent-onset uveitis. However, T cells removed from the eye were highly susceptible to both spontaneous and Fas ligand-induced apoptosis in vitro. AqH from patients with uveitis had no modulatory effect on Fas ligand-induced apoptosis, but strongly suppressed survival factor deprivation-induced apoptosis. In contrast, noninflammatory AqH from patients undergoing cataract surgery had no modulatory effects on apoptosis at all. These data suggest that triggering of the Fas pathway is diminished in uveitis, and also that homeostatic resolution through survival factor deprivation-induced apoptosis is inhibited by factors present in AqH. The most widely recognized pathways, common -chain cytokines and type I IFNs, did not contribute to AqH-mediated T cell survival. High levels of both IL-6 and soluble IL-6R were found in AqH. IL-6 alone did not induce T cell survival, because IL-6R expression on T cells in AqH was too low to facilitate signaling. However, combinations of IL-6 and soluble IL-6R were highly effective inhibitors of T cell apoptosis, suggesting that the trans-signaling pathway is likely to be a key mediator of T cell apoptosis inhibition mediated by uveitis AqH.

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