RESEARCH ARTICLE CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis

CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epi-topes) represent a principal player in chronic immune activation, which is known to amplify immu-nopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immuno-pathology, and the response to tumor necrosis factor-α inhibitor therapy. The frequency of auto-reactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules com-plexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients whowere submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control). The percentage of apoptotic epitope-specific CD8+ T cells was sig-nificantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necro-sis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that theymay potentially represent a predictive biomarker of re-sponse to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients