Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T (T_reg) cells, and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2–based therapeutics with improved T_reg cell specificity. From a panel of rationally designed murine IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced T_reg cell selectivity due to increased dependence on the IL-2 receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective T_reg cell enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall T_reg cell growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared with Fc-fused wild-type IL-2. Preferential T_reg cell enrichment was also observed in the presence of activated pathogenic T cells in the pancreas of nonobese diabetic (NOD) mice, despite a loss of T_reg cell selectivity in an IL-2R proximal response. These properties facilitated potent and extended resolution of NOD diabetes with infrequent dosing schedules.

白细胞介素 2 (IL-2) 控制调节性 T (T _reg ) 细胞的稳态和功能，IL-2 通路中的缺陷导致多种自身免疫性疾病。尽管重组 IL-2 疗法在某些炎症条件下有效，但 IL-2 也能激活炎症效应器反应的能力突出了对基于 IL-2 的疗法的需求，该疗法具有改进的 T _reg细胞特异性。从一组合理设计的鼠类 IL-2 变体中，我们鉴定了由于对 IL-2 受体成分 CD25 的依赖性增加而具有降低的效力和增强的 T _reg细胞选择性的IL-2 突变蛋白。作为 Fc 融合同源二聚体，最佳 Fc.IL-2 突变蛋白诱导选择性 T _reg细胞富集和效应细胞在宽剂量范围内的激动作用降低。此外，尽管是较弱的激动剂，但与 Fc 融合野生型 IL-2 相比，由于受体介导的 Fc.IL-2 突变蛋白清除率降低，因此总体 T _reg细胞生长更大且更持久。尽管在 IL-2R 近端反应中失去了 T _reg细胞选择性，但在非肥胖糖尿病 (NOD) 小鼠的胰腺中存在活化的致病性 T 细胞时，也观察到了优先的 T _reg细胞富集。这些特性通过不频繁的给药方案促进了 NOD 糖尿病的有效和扩展解决方案。