TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1.
T-helper type 17 cells (T(H)17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. T(H)17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-gamma. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)-alpha in retinal cells, suggesting a mechanism by which T(H)17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-gamma and inhibited proliferation of T(H)17. These findings suggest that T(H)1 cells may mitigate uveitis by antagonizing the T(H)17 phenotype through the IFN-gamma-mediated induction of IL-27 in target tissue. The finding that IL-2 promotes T(H)17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of T(H)17 by IFN-gamma and/or IL-27 could be used for the treatment of chronic inflammation.
Amadi-Obi
Ahjoku
A
Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Yu
Cheng-Rong
CR
Liu
Xuebin
X
Mahdi
Rashid M
RM
Clarke
Grace Levy
GL
Nussenblatt
Robert B
RB
Gery
Igal
I
Lee
Yun Sang
YS
Egwuagu
Charles E
CE
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D050794:STAT1 Transcription Factor / Q000502:physiology*; D015423:Scleritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014605:Uveitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
D006131:Growth Inhibitors; C486767:Il27 protein, mouse; D007376:Interleukin-2; D007378:Interleukins; C464565:MYDGF protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse