Attenuated IL-2 Signaling Rewires Transcriptional and Metabolic Programs in T Cells to Enable Coupling Proliferation and Stemness. Attenuated IL-2 Signaling Rewires Transcriptional and Metabolic Programs in T Cells to Enable Coupling Proliferation and Stemness

Interleukin-2 (IL-2) is a fundamental cytokine that controls the proliferation and differentiation of T cells1. Its direct administration in vivo has conferred durable, complete responses in patients with metastatic melanoma and renal cell cancer, while it is also used to expand tumor-infiltrating lymphocytes (TILs) in vitro for adoptive cell therapy (ACT)2. Unfavorable properties of IL-2 including terminal differentiation of effector T cells3-6, induction of activation-induced cell death (AICD)2, 7, 8, expansion of regulatory T (Treg) cells, and toxicity at high doses, have driven the development of IL-2 variants with modified biological properties9-13. However, how cytokine modifications alter cell fate decisions is not well understood. Here, taking a systems biology approach we have comprehensively elucidated how a non CD25-binding, IL-2-biased agonist (IL-2v)14 reprograms signaling, transcriptional, and metabolic networks of CD8+ T cells in vitro to favor stemness while simultaneously driving expansion and functionality. Such "expansion-stemness state" defines metabolically fit CD8+ T cells capable of superior persistence and tumor control. These findings broaden our fundamental understanding of the effects of IL-2v on T-cell biology and provide an investigational framework for the rational development and evaluation of cytokine variants with clinical relevance. Overall design: OT1 T cells cultured for 10 days with 5 and 50 IU/mL of IL-2v, IL-2 and IL‑15

白细胞介素-2（Interleukin-2, IL-2）是调控T细胞增殖与分化的核心细胞因子¹。其体内直接给药可使转移性黑色素瘤与肾细胞癌患者获得持久完全应答，同时也可在体外扩增肿瘤浸润淋巴细胞（tumor-infiltrating lymphocytes, TILs）用于过继细胞治疗（adoptive cell therapy, ACT）²。IL-2存在诸多不利特性：包括诱导效应T细胞终末分化³⁻⁶、引发激活诱导的细胞死亡（activation-induced cell death, AICD）²,7,8、扩增调节性T（regulatory T, Treg）细胞，以及高剂量下的毒性，这些推动了具备修饰后生物学特性的IL-2变体的研发⁹⁻¹³。然而，细胞因子修饰如何改变细胞命运抉择的机制仍不甚明晰。本研究采用系统生物学策略，全面阐明了不结合CD25、偏向IL-2βγ的激动剂（non CD25-binding, IL-2βγ-biased agonist, IL-2v）¹⁴在体外如何重编程CD8阳性T细胞的信号转导、转录与代谢网络，在促进其扩增与功能活性的同时，强化其干细胞特性。这种“扩增-干细胞状态”定义了代谢适配的CD8阳性T细胞，这类细胞具备更优异的体内持久性与肿瘤抑制能力。本研究拓展了我们对IL-2v影响T细胞生物学效应的基础认知，并为合理开发与评估具有临床转化价值的细胞因子变体提供了研究框架。实验整体设计：将OT1 T细胞在分别含有5 IU/mL与50 IU/mL的IL-2v、IL-2及IL-15的培养基中培养10天。