Thymic self-recognition-mediated TCR signal strength modulates antigen-specific CD8⁺T cell pathogenicity in non-obese diabetic mice

Our understanding of autoimmune diabetes underscores the critical involvement of CD8⁺T cells recognizing islet-specific antigens. However, the influence of thymic positive selection on diabetogenic CD8⁺T cell development remains unclear. Using CD5 marker representing T-cell receptor (TCR) signal strength, we illustrated that naïve CD5^hiCD8⁺T cells of non-obese diabetic (NOD) mice with enhanced TCR signals displayed predisposed differentiated/memory T cell traits with increased activation and proliferation upon TCR stimulation, compared to CD5^locounterparts. Additionally, CD5^hiCD8⁺T cells exhibited gene expression landscape similar to effector T cells and exacerbated disease in transfer model. Interestingly, the protective effects of transgenic phosphatase Pep expression, which lowers TCR signaling and diabetes incidence, were abolished in NOD strain 8.3 with high CD5 expression linked to increased thymic positive selection. Strikingly, TCR repertoire analysis identified higher frequencies of autoimmune disease-related clonotypes in naïve CD5^hiCD8⁺cells, supporting that distinct effector functions arise from intrinsic TCR repertoire differences. Overall, CD5^hiCD8⁺clones may be potential targets for autoimmune diabetes treatment.