IL-23 drives uveitis by acting on a population of tissue-resident entheseal T cells
Robert Hedley, … , Andrew D. Dick, David A. Copland
Robert Hedley, … , Andrew D. Dick, David A. Copland
Published August 28, 2025
Citation Information: JCI Insight. 2025;10(19):e182616. https://doi.org/10.1172/jci.insight.182616.
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Research Article Immunology Inflammation Ophthalmology

IL-23 drives uveitis by acting on a population of tissue-resident entheseal T cells

Abstract

Recurrent acute anterior uveitis is a frequent extra-articular manifestation of the axial spondyloarthropathies (AxSpA): chronic inflammatory diseases affecting the spine, enthesis, peripheral joints, skin, and gastrointestinal tract. Pathology in AxSpA has been associated with local tissue-resident populations of IL-23 responsive lymphoid cells. Here we characterize a population of ocular T cell defined by CD3+CD4–CD8–CD69+γδTCR+IL-23R+ that reside within the anterior uvea as an ocular entheseal analogue of the mouse eye. Localized cytokine expression demonstrates that uveal IL-23R+ IL-17A–producing cells are both necessary and sufficient to drive uveitis in response to IL-23. This T cell population is also present in humans, occupying extravascular tissues of the anterior uveal compartment. Consistent with the concept of IL-23 as a unifying mediator in AxSpA, we present evidence that IL-23 can also act locally on tissue resident T cells in the anterior compartment of the eye at sites analogous to the enthesis to drive ocular inflammation.

Authors

Robert Hedley, Amy Ward, Colin J. Chu, Sarah E. Coupland, Serafim Kiriakidis, Peter C. Taylor, Stephanie G. Dakin, ORBIT Research Consortium, Christopher D. Buckley, Jonathan Sherlock, Andrew D. Dick, David A. Copland

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Figure 4

CD3+γδTCR+IL-23R+ are both necessary and sufficient to drive IL-23–mediated inflammation.

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CD3+γδTCR+IL-23R+ are both necessary and sufficient to drive IL-23–media...
C57BL/6J and B6.Cg-Thy1 (Rag2-KO) received intravitreal injection of 1 × 1011 vector genomes of ShH10_IL23 or ShH10_GFP vectors. Clinical monitoring (fundus and OCT) performed until day 12. Eyes were enucleated and prepared for flow cytometry to quantify immune cell infiltration in the anterior uvea and retina. (A) Representative clinical images show perivascular sheathing (white arrowheads) and vitreous infiltrate present in C57BL/6J eyes receiving ShH10_IL23 only. (B) Total live CD45+ cell counts (anterior uvea or retina) from C57BL/6J or Rag2-KO mice at day 12 (naive [n = 4]; ShH10_GFP [n = 6–9] or ShH10_IL-23 [n = 6–13]; data combined from 2 independent experiments). IL-23R–eGFP (+/–) mice were bilaterally injected with ShH10_IL23 (1 × 1011 vector genomes) and allocated to groups (n = 6) for repeated oral dosing with fingolimod (FTY720; 10 mg/kg) or vehicle control, administered on alternate days following AAV injection. On day 12, eyes were evaluated using clinical imaging and enucleated for flow cytometric analysis of cell infiltrate. (C) Representative images show inflammation absent in eyes receiving FTY720 treatment. (D and E) Total live CD45+ counts in the anterior uvea and retina, and CD3+ and γδTCR+IL-23R+ cells in the anterior uvea. (F) Relative frequency of γδTCR+ expressing Vγ1, Vγ4, or Vγ6 in naive (n = 6) and ShH10_IL23 injected eyes receiving vehicle or FTY720 treatment (n = 12). (G and H) Following ex vivo restimulation, representative gating of anterior uvea γδTCR+IL-23R+ cells in response to ShH10_IL23 to show relative frequency of IL-17A–expressing cells is equivalent between the FTY720 and vehicle treatment groups. Statistical analysis was performed with 1-way ANOVA. Data expressed as means ± SEM. ns = not significant. ** = P < 0.01, *** = P < 0.001 and **** =P < 0.0001 (C–E). Mann-Whitney test; * = P < 0.05 (H).