Mechanistic Insights from Human Studies in Axial Spondyloarthritis: A T Cell Story.

PURPOSE OF REVIEW: Ankylosing spondylitis (AS) represents the archetype of the spondyloarthritis family defined by its strong association with HLA-B*27. While genetic susceptibility has long pointed toward adaptive immunity, the precise cellular pathways linking MHC class I alleles to axial inflammation have remained an enigma. In this article, we review the fundamental molecular and clinical evidence positioning CD8  and CD4  T cells as primary pathogenic drivers of disease in the HLA-B*27 +  patients. RECENT FINDINGS: High-throughput T cell receptor (TCR) sequencing and single-cell RNA sequencing have identified “public” TRAV21/TRBV9 TCRs, that are expanded in the inflamed joints and eyes of patients. These clones initiate disease via molecular mimicry, recognizing both microbial and self-peptides presented by HLA-B*27. The clinical success of seniprutug, a monoclonal antibody selectively targeting TRBV9 +  T cells, provided the first proof-of-concept that these specific clonotypes drive clinical disease. Furthermore, high-resolution profiling has identified CD4 Th17 cells as the dominant producers of IL-17 within the synovial niche, providing a cellular basis for the efficacy of IL-17A and IL-17F blockade. AS is a disease characterized by convergent cross-reactive T cell responses. The identification of pathogenic TCR signatures and their candidate cognate antigens has moved diagnostics and management toward precision medicine.