白介素 2 (IL-2) 有望用于治疗癌症和自身免疫性疾病，但其高剂量使用与全身免疫毒性有关。差异性 IL-2 受体 (IL-2R) 调节可能会影响 IL-2 刺激后的细胞功能，可能诱导与 IL2RB 低效突变患者类似的细胞变化，从而表现出多器官自身免疫。在这里，我们发现，持续高剂量 IL-2 刺激人类淋巴细胞会显着降低 IL-2Rβ 表面表达，尤其是 T 细胞上的表达，导致 IL-2R 信号传导受损，而这与高 IL-2Rα 基线表达相关。 NK 细胞中的 IL-2R 信号传导得以维持。 CD4 T 细胞，尤其是调节性 T 细胞比 CD8 T 细胞受到更广泛的影响，这与 IL-2 反应性的谱系特异性差异一致。鉴于高剂量 IL-2 刺激的细胞和来自 IL-2Rβ 缺陷患者的细胞的细胞特征相似，在 IL 期间出现临床不良事件时应考虑持续 IL-2 刺激对 IL-2R 信号传导的影响-2 疗法。版权所有 © 2024。由 Elsevier Inc. 出版。

Interleukin-2 (IL-2) holds promise for the treatment of cancer and autoimmune diseases, but its high-dose usage is associated with systemic immunotoxicity. Differential IL-2 receptor (IL-2R) regulation might impact function of cells upon IL-2 stimulation, possibly inducing cellular changes similar to patients with hypomorphic IL2RB mutations, presenting with multiorgan autoimmunity. Here, we show that sustained high-dose IL-2 stimulation of human lymphocytes drastically reduces IL-2Rβ surface expression especially on T cells, resulting in impaired IL-2R signaling which correlates with high IL-2Rα baseline expression. IL-2R signaling in NK cells is maintained. CD4+ T cells, especially regulatory T cells are more broadly affected than CD8+ T cells, consistent with lineage-specific differences in IL-2 responsiveness. Given the resemblance of cellular characteristics of high-dose IL-2-stimulated cells and cells from patients with IL-2Rβ defects, impact of continuous IL-2 stimulation on IL-2R signaling should be considered in the onset of clinical adverse events during IL-2 therapy.Copyright © 2024. Published by Elsevier Inc.