Abstract
Advances in T cell receptor (TCR) profiling techniques have substantially improved our ability to investigate T cell responses to antigens that are presented on HLA class I and class II molecules and associations between autoimmune T cells and rheumatic diseases. Early-stage studies in axial spondyloarthritis (axSpA) identified disease-associated T cell clonotypes, benefiting from the relative genetic homogeneity of the disease. However, both the genetic and the T cell immunological landscape are more complex in other rheumatic diseases. The diversity or redundancy in the TCR repertoire, epitope spreading over disease duration, genetic heterogeneity of HLA genes or other loci, and the diversity of epitopes contributing to disease pathogenesis and persistent inflammation are all likely to contribute to this complexity. TCR profiling holds promise for identifying key antigenic drivers and phenotypic T cell states that sustain autoimmunity in rheumatic diseases. Here, we review key findings from TCR repertoire studies in axSpA and other chronic inflammatory rheumatic diseases including psoriatic arthritis, rheumatoid arthritis, systemic lupus erythematosus and Sjögren syndrome. We explore how TCR profiling technologies, if applied to better controlled studies focused on early disease stages and genetically homogeneous subsets, can facilitate disease monitoring and the development of therapeutics targeting autoimmune T cells, their cognate antigens, or their underlying biology.
Key points
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Next-generation sequencing has enabled development of comprehensive and accurate T cell receptor profiling, allowing studies to search for expanded T cell clonotypes suggestive of shared antigenic drivers.
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Using these approaches, expanded CD8 T cell clonotypes bearing highly similar T cell receptor (TCR) β-chains and α-chains have been identified in a high proportion of patients with ankylosing spondylitis, and this information has been used to identify expanded T cell clonotypes potentially involved in the pathogenesis of the disease.
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TCR repertoire studies in other rheumatic diseases, including psoriatic arthritis, rheumatoid arthritis, systemic lupus erythematosus and Sjögren syndrome, have not found consistently expanded T cell clonotypes, although evidence of T cell expansions including at sites of inflammation have been reported.
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Further studies focusing on early disease and more clinically, genetically and immunologically homogeneous cohorts might provide more informative to identify expanded aetiopathogenic T cell clonotypes.
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Garrido-Mesa, J., Brown, M.A. Antigen-driven T cell responses in rheumatic diseases: insights from T cell receptor repertoire studies. Nat Rev Rheumatol 21, 157–173 (2025). https://doi.org/10.1038/s41584-025-01218-9
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DOI: https://doi.org/10.1038/s41584-025-01218-9
