Background/Purpose: Antigen-specific therapies offer a promising approach to selectively modulating autoimmune responses without broad immunosuppression. Strong associations with specific Class I HLA alleles in ankylosing spondylitis (AS) with a linkage to HLA-B*27:05 (Odds ratio of 62) and birdshot uveitis (BU) with a linkage to HLA-A*29:02 (Odds ratio of 157) suggest a role for CD8⁺ T cells, yet the causative autoantigens remain unknown. TScan’s proprietary TargetScan platform offers an unbiased high-throughput method to identify the natural targets of disease-relevant T cell receptors and aid in the development of antigen specific tolerizing modalities.

Methods: We isolated CD8⁺ T cells from synovial fluid of patients with AS and aqueous humor or vitreous humor from patients with BU. Single-cell TCR sequencing identified 42 unique paired α/β TCR sequences from the ankylosing spondylitis samples and 113 clonotypes from the BU samples. These TCRs, along with 14 previously published TCRs from AS patients, were gene synthesized and screened using the TargetScan platform against a comprehensive cell library representing the full human proteome presented naturally by cells engineered to express the disease associated HLA allele (HLA-B*27:05 for AS, HLA-A*29:02 for BU). Screening revealed multiple putative autoantigen targets which were subsequently evaluated for disease relevance.

Results: Using this approach, we identified over 10 putative Class I–restricted T cell targets for AS and two for BU. These targets were validated through orthogonal assays, including functional T cell activation, and exhibited expression patterns consistent with disease-relevant tissues. Minimal epitopes for each target were mapped to define the core sequences required for TCR recognition. Their identification provides new insight into the antigenic drivers of these conditions and highlights potential avenues for the development of antigen-specific therapeutics.

Conclusion: TScan’s discovery platform enables the identification of novel Class I-restricted autoantigens in autoimmune diseases where no targets were previously known, filling a critical gap in the understanding of T cell-driven pathology. This technology provides a foundation for the development of antigen-specific therapeutics, including tolerogenic approaches aimed at restoring immune homeostasis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targetscan-platform-identifies-targets-of-cd8-t-cells-in-ankylosing-spondylitis-and-birdshot-uveitis/