From thymic education to the body’s last line of defense, this episode unpacks peripheral immune tolerance—the active backup that prevents autoimmunity and quiets benign exposures. We trace the Nobel-recognized discovery of FOXP3 and the master regulator role of regulatory T cells, outline the four intrinsic mechanisms that restrain self-reactive T cells, and explore the roles of tolerogenic dendritic cells and lymph node stromal cells. Join us as we discuss how these insights illuminate new therapeutic avenues for autoimmune disease and beyond, and reflect on what the 2025 Nobel work means for immunology.

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