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 1

Tissue-resident CD3+IL-23R+ T cells are found in the mouse anterior uvea.

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Tissue-resident CD3+IL-23R+ T cells are found in the mouse anterior uvea...
Naive B6(Cg)-Tyrc-2J/J (albino) mice were perfused, and intact globes optically cleared, immunolabelled with CD3e and DAPI. (A) Lightsheet Z.1 acquired, immunofluorescent whole mount images (top left), rotated 90° (top right), rotated 180° (bottom left), and rotated 270° (bottom right). 3D rendered image shows expression of tissue autofluorescence (white) and CD3e (purple). Coexpression of CD3 and nuclei observed within different regions including the peripheral cornea, limbal sclera ,and ciliary body. Images captured at ×10 magnification. Scale bar: 100 μm. CP, ciliary process; CB, ciliary body; S, sclera; I, iris; C, cornea. (B) Immunofluorescence image of anterior tissue section from perfused albino mouse demonstrates presence of CD45+CD3+ T cells within extravascular tissues including the trabecular meshwork, ciliary body and sclera. Image captured at ×20 magnification. Dashed blue line, the inner limit of the sclera; dashed white line, trabecular meshwork; X, Schlemm’s canal; CP, ciliary process; CB, ciliary body; S, sclera; and R, retina. (C) CD4+ and CD8+ (single positive) cells are restricted to the juxtacanalicular tissue (JCT) region of the trabecular meshwork, proximal to the inner wall of Schlemm’s canal. Colored arrows indicating T cell subtypes; CD3+ (green), CD4 (red), and CD8+ (purple). (D) Sections also highlighted CD3+CD4–CD8– (double-negative T cells) in the region of ciliary body proximal to the limbal sclera. (E–H) Sections taken from naive IL-23R–eGFP (+/–) reporter mice IL-23R+ cells are evident within the limbal sclera, specifically the transitional region of the sclera to ciliary body (E) and the transitional region from episclera (ES) to stromal sclera (SS) and not the vascular ES (F), the folding of the inner ciliary body (G), and posterior border layer of the iris (H). Nuclei (blue) and IL-23R–eGFP (green). Red square highlights region of tissue magnified in adjacent image (C and E–H).