PROJECT SUMMARY My career goal is to better understand systemic diseases in rheumatology by examining the mechanisms of ocular inflammation and determining which mechanisms are specific to the eye and which are shared with other organs, particularly the joint. This five-year proposal for a Mentored Clinical Scientist Research Career Development Award will help me mature into a productive, independent academic investigator in the field of ocular rheumatology. Advances in this area should complement the body of work in the field to allow for a more comprehensive understanding of systemic autoimmune disorders. Axial spondyloarthritis is strongly associated with HLA-B27 and has frequent extra-articular manifestations such as anterior uveitis, an inflammatory ocular disease that can lead to cataract, glaucoma, and permanent vision loss. While discrimination between pathogenic and bystander immune cells in rheumatologic diseases has been challenging, the intrinsic immune privilege of the eye increases the enrichment for pathogenic cell types. Therefore, studying ocular immune cells and the corresponding populations in the peripheral blood provides a novel opportunity to understand both organ-specific and systemic mechanisms of disease pathogenesis. Using single-cell RNA sequencing (scRNAseq) in three individuals, we have preliminarily identified two subsets of CD8 T cells that collectively accounts for ~50% of all CD8 T cells within the eye during HLA-B27+ anterior uveitis. While both types of CD8 T cells share a transcriptional program, such as expression of the surface receptor CD161, the antigen-specificity is distinct for each population. The first population is a conventional polyclonal CD8 T cell population that recognizes viral antigens, among others, but is able to express IL-17 and therefore have been termed Tc17 cells. In contrast, the second population is an unconventional T cell population that predominantly uses a single T cell receptor gene segment that specifically recognizes metabolites of riboflavin synthesis and are called mucosal-associated invariant T (MAIT) cells. Given the difference in antigen-specificity, we hypothesize that these two CD8 T cell types serve redundant roles in an antigen- independent mechanism of inflammation. We propose to establish whether MAIT or Tc17 cells play a central role in HLA-B27+ anterior uveitis by using scRNAseq and multidimensional flow cytometry to assess (1) whether one or both CD161+ CD8 T cell subtypes are conserved in HLA-B27+ anterior uveitis, (2) what mechanisms of activate these cells within the eye, and (3) whether one or both of these subsets are dysregulated in the circulation prior to entry into the eye. Through successful completion of this research, undergoing the didactic training, and receiving guidance from a multidisciplinary group of experts, I plan to launch my career as an independent translational researcher investigating the ocular manifestations of rheumatologic diseases...