IL-23 drives uveitis by acting on a population of tissue-resident entheseal T cells
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
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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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 5

The human anterior uvea contains tissue resident CD3+ cells.

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The human anterior uvea contains tissue resident CD3+ cells. FFP tissue ...
FFP tissue sections prepared from an enucleated human eye with a healthy anterior chamber were costained with antibodies to CD3 (red), CD34 (blue), podoplanin (green), and Hoechst nuclear stain (gray). (A–E) Representative confocal immunofluorescence (IF) images showing extravascular location of CD3+ T cells in the ciliary processes (A); ciliary body proximal to the longitudinal ciliary muscles (B); within the ciliary region of the iris proximal to the anterior epithelium and dilator muscles of the posterior border layer (C); at the border of the ICA and arranged alongside PDPN+ trabeculae cells (D); and in the cribriform layer of the trabecular meshwork (TM) adjacent to the inner wall of Schlemm’s canal (E). AC, anterior chamber; BV, blood vessel; CNPE, ciliary nonpigmented epithelium; CPE, ciliary pigmented epithelium; CS, ciliary stroma; CS+M, ciliary stroma and muscle; IAE, iris anterior epithelium; IPPE, iris pigmented epithelium; IR, iris root; ICA and red arrowheaded line, iridocorneal angle; CM, cribriform meshwork; IWE, inner wall epithelium of Schlemm’s canal; OWE, outer wall epithelium of Schlemm’s canal; X, the lumen of Schlemm’s canal. Scale bar: 20 mm. (F and G) Representative immunofluorescence image showing merged expression of second harmonic resonance (SHR) collagen fibers and nuclei (gray), and CD3 (red) within a major ciliary process. Hashed squares highlight magnified region. Photographs detailing dissection of the major ciliary process from healthy human anterior uvea for whole mount staining, with SHR image showing merged expression of Col IV and CD3. Scale bar: 50 μm. (H) Images to show merged expression of SHR collagen fibers, CD3, and RORγt (blue). Hashed square highlights magnified region. All SHR images captured at ×40 magnification.