A deeper understanding and leverage of the subtle differences in cytokine:receptor binding, receptor usage and expression, and signaling pathways are giving rise to promising advances in targeting cytokines in both cancer and autoimmunity, such as recent work by Garcia, Bluestone, and colleagues [16] who engineered a synthetic IL-2R–IL-2 pair that effectively boosted engineered CD4+ and CD8+ T cell expansion in vivo and in vitro while limiting off-target effects and toxicity. This evidence concerns the gene CD8A and Autoimmunity.