The critical role of IL-23 receptor positive T cells in the pathogenesis of anterior uveitis associated with spondyloarthropathy

The spondyloarthropathies (SpAs) are a group of chronic inflammatory diseases which predominantly affect the joints of the axial skeleton. However, many patients with SpA may have extra-articular manifestations within the skin and gut. Pathology of SpA in all of these tissues has been shown in recent studies to be driven by local resident populations of interleukin (IL)-23 responsive cells. The eye is also involved in these diseases, with uveitis occurring in up to 40% of patients with SpA. Therefore, it is feasible that a resident population of IL-23 responsive cells could also exist within the eye. Recently, systemic overexpression of IL-23 in mice has shown the accumulation of a small number of γδ T cells proximal to the anterior uvea. However, although work has been done to characterize resident leukocyte populations within the anterior compartment of the eye there has been no documentation of resident lymphoid cells in these tissues and there is no evidence suggesting the presence of a sentinel cell capable of responding to IL-23. In this study I document for the first time that a diverse population of T cells is present in the extravascular tissues of the anterior compartment of the eye in both mice and humans. I also identify the presence of a resident IL‐23R+CD3+CD4-CD8- γδ T cell in the anterior compartment of the eye, providing a potential explanation for why IL-23 is capable of affecting all of these distal sterile tissues. I then stimulated these cells to show that they have functional IL-23R activity and that IL-23 is sufficient to drive uveitis in the absence of any pro-inflammatory mediator. I achieve this in vivo in mice through a novel mechanism enabling the sustained localized overexpression of IL-23 in the inner eye by adeno-associated virus gene transfer. Since I could not do this in humans, I instead stimulated human eye tissue with IL-23 in vitro. Here I was able to show that that IL-23 is sufficient to drive the expression of several downstream pro-inflammatory cytokines by these cells. Consistent with the concept of IL-23 being a unifying factor in SpA, I show that like the gut, skin, and joints - IL-23 can also act locally on a resident IL-23 responsive cells to drive pathology within the eye.