Inhibition of T cell apoptosis in the aqueous humor of patients with uveitis by IL-6/soluble IL-6 receptor trans-signaling.
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 gamma-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.
Curnow
S John
SJ
Department of Rheumatology, Medical Research Council Centre for Immune Regulation, Division of Immunity and Infection, Medical School, The University of Birmingham, UK. s.j.curnow@bham.ac.uk
Scheel-Toellner
Dagmar
D
Jenkinson
Will
W
Raza
Karim
K
Durrani
Omar M
OM
Faint
Jeff M
JM
Rauz
Saaeha
S
Wloka
Kaska
K
Pilling
Darrell
D
Rose-John
Stefan
S
Buckley
Christopher D
CD
Murray
Philip I
PI
Salmon
Mike
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis; D001082:Aqueous Humor / Q000276:immunology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D014605:Uveitis / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D019014:fas Receptor