Background/Purpose: TRBV9 depletion is a novel strategy for the treatment of HLA-B27⁺ axial spondyloarthritis (axSpA) and has achieved clinical remission in at least one patient. Anti-TRBV9 antibodies eliminate pathogenic T cells that utilize the TRBV9 gene segment to construct their T cell receptor (TCR). As the amino acids encoded by TRBV9 are not involved in antigen recognition, we hypothesized that alternative TRBVs could be employed to generate a TCR with similar antigen specificity and pathogenicity.

Methods: HLA-B27⁺ acute anterior uveitis is associated with axSpA. We therefore examined single cell TCR sequencing of ocular and blood cells in HLA-B27⁺ acute anterior uveitis to identify non-TRBV9 TCRs that would have similar antigen-specificity. We validated our top TCR candidate using an in vitro platform to test shared antigen specificity. Lastly, we sorted CD8 T cells based on cell surface receptors and antigen specificity to enrich for pathogenic CD8 T cells and determine the variability of TRBV gene segment usage for antigen recognition.

Results: We found a TRBV5-5⁺ TCR that was clonally expanded and enriched ~100 fold in the eye over the blood during HLA-B27⁺ acute anterior uveitis. This TRBV5-5⁺ TCR shared reactivity with pathogenic TRBV9⁺ TCRs to the YeiH bacterial antigen. Single cell TCR sequencing of sorted blood CD8 T cells identified multiple TRBVs (TRBV5-4, TRBV5-5, and TRBV7-3) incorporated into putative pathogenic TCRs.

Conclusion: Collectively, our data suggest that TRBV9 is dispensable for antigen recognition by pathogenic TCRs in axSpA and that patients may contain non-TRBV9 TCRs with similar antigen specificity and pathogenic potential. These alternative TRBVs would not be targeted by anti-TRBV9 antibodies, providing a key limitation to this novel strategy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/single-cell-tcr-sequencing-suggests-potential-limitations-of-trbv9-depleting-therapies-in-axial-spondyloarthritis/