Checkpoint Blockade Selects Innate-Programmed Cytotoxic T Cells with Pathogenic TCR Features in Immune-Related Arthritis 2309982

Introduction T cell immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), including inflammatory arthritis. The cellular and molecular mechanisms underlying irAE arthritis are not well understood. We hypothesize that a particular subset of CD8 T cells expands in irAE arthritis and that these clones possess unique TCR sequences. Methods Single-cell RNA, paired TCR sequencing and computational approach was applied to analyze clonal, transcriptional, and CDR3 biophysical features of circulating CD8 T cells before and after anti—PD-1 therapy. Results Among the cells collected from patients with irAE arthritis, we identified a population of clonally expanding PRF1+ CD8 effector T cells displaying an innate-like inflammatory and metabolically active phenotype. This cell population expresses cytotoxic effector genes, innate sensing, and metabolic pathways. Remarkably, within this population, TCR repertoires exhibited significantly greater hydrogen-bonding in the CDR3 hypervariable region than in no-irAE controls, suggesting distinctive antigen specificity and binding stability. This feature was present before the ICI treatment. It was further amplified after the therapy, consistent with dynamic clonal selection under checkpoint blockade. Conversely, expanding CD8 T cell clones from patients without irAEs exhibited lower hydrogen bond propensity both before and after treatment. Furthermore, irAE arthritis-associated clonotypes also showed increased hydrophobicity in the central CDR3 region. These regions consisted of shorter CDR3 sequences, indicating a compact structural architecture that promotes stable, potentially promiscuous peptide-MHC interactions. Conclusion Our findings suggest that checkpoint blockade selectively expands innate-programmed cytotoxic CD8 T cells with structurally optimized TCRs, promoting autoreactive effector responses and defining integrated cellular and TCR biophysical determinants of irAE susceptibility. Funding Source NIH AI125640 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)