Activation of OX40 augments Th17 cytokine expression and antigen-specific uveitis.
Uveitis is a major and common cause of visual disability. Recent studies have shown that Th17 cells are implicated in the pathogenesis of this serious intraocular disorder. Activated T cells express an inducible costimulatory molecule called OX40, and OX40 in turn promotes the activation and proliferation of these lymphocytes. Nevertheless, it is unclear whether OX40 plays a vital role in enhancing the effector function of Th17 cells as well as the severity of uveitis. In this study, we demonstrated an increase of OX40 transcription in ovalbumin-induced uveitis, whereas anti-OX40L antibody substantially inhibited the antigen-specific ocular inflammation. Next, results from flow cytometry showed that activated Th17 cells expressed OX40, and OX40-activating antibody significantly augmented the production of Th17 cytokines in vitro. To validate the impact of OX40 in vivo, we stimulated ovalbumin-specific T cells with the OX40-activating antibody. Compared to donor cells without OX40 activation, adoptive transfer of OX40-stimulated lymphocytes elicited more severe ocular inflammation. Furthermore, an interleukin-17-neutralizing antibody attenuated OX40-mediated uveitis. In conclusion, our findings suggest that activation of OX40 augments Th17 cell function and thereby contributes to ocular inflammation. This study thus enhances our knowledge of costimulatory molecule-mediated immunopathological mechanisms of uveitis and suggests a future therapeutic strategy to treat uveitis by the targeting of OX40.
Departments of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA. zhangzi@ohsu.edu
Zili
Z
Zhang
Wenwei
W
Zhong
David
D
Hinrichs
Xiumei
X
Wu
Andrew
A
Weinberg
Mark
M
Hall
Doran
D
Spencer
Keith
K
Wegmann
James T
JT
Rosenbaum
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000941:Antigens / Q000009:adverse effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D007167:Immunotherapy; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053278:OX40 Ligand; D053262:Receptors, OX40 / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000494:pharmacology; D014605:Uveitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy
D057134:Antibodies, Neutralizing; D000941:Antigens; D016207:Cytokines; D000939:Epitopes; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors