Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada.
Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
J Immunol. 2022 Jan 1;208(1):155-168. doi: 10.4049/jimmunol.2100452. Epub 2021 Dec 6.
CD8 memory T (T) cells play a critical role in immune defense against infection. Two common γ-chain family cytokines, IL-2 and IL-7, although triggering the same mTORC1-S6K pathway, distinctly induce effector T (T) cells and T cells, respectively, but the underlying mechanism(s) remains elusive. In this study, we generated /and αknockout (KO)/OTI mice. By using genetic and pharmaceutical tools, we demonstrate that IL-7 deficiency represses expression of FOXO1, TCF1, p-AMPKα1 (T), and p-ULK1 (S) and abolishes T cell memory differentiation in KO T cells after rLmOVA infection. IL-2- and IL-7-stimulated strong and weak S6K (IL-2/S6K and IL-7/S6K) signals control short-lived IL-7RCD62LKLRG1 T and long-term IL-7RCD62LKLRG1 T cell formations, respectively. To assess underlying molecular pathway(s), we performed flow cytometry, Western blotting, confocal microscopy, and Seahorse assay analyses by using the IL-7/S6K-stimulated T (IL-7/T) and the control IL-2/S6K-stimulated T (IL-2/T) cells. We determine that the IL-7/S6K signal activates transcriptional FOXO1, TCF1, and Id3 and metabolic p-AMPKα1, p-ULK1, and ATG7 molecules in IL-7/T cells. IL-7/T cells upregulate IL-7R and CD62L, promote mitochondria biogenesis and fatty acid oxidation metabolism, and show long-term cell survival and functional recall responses. Interestingly, AMPKα1 deficiency abolishes the AMPKα1 but maintains the FOXO1 pathway and induces a metabolic switch from fatty acid oxidation to glycolysis in α KO IL-7/T cells, leading to loss of cell survival and recall responses. Taken together, our data demonstrate that IL-7-stimulated weak strength of mTORC1-S6K signaling controls T cell memory via activation of transcriptional FOXO1-TCF1-Id3 and metabolic AMPKα1-ULK1-ATG7 pathways. This (to our knowledge) novel finding provides a new mechanism for a distinct IL-2/IL-7 stimulation model in T cell memory and greatly impacts vaccine development.
CD8 记忆 T（T）细胞在抗感染免疫防御中发挥着关键作用。两种常见的 γ 链家族细胞因子，IL-2 和 IL-7，尽管触发相同的 mTORC1-S6K 途径，但分别明显诱导效应 T（T）细胞和 T 细胞，但潜在机制仍不清楚。在这项研究中，我们生成了 / 和 α 敲除（KO）/OTI 小鼠。通过使用遗传和药物工具，我们证明 IL-7 缺乏会抑制 FOXO1、TCF1、p-AMPKα1（T）和 p-ULK1（S）的表达，并在 rLmOVA 感染后消除 KO T 细胞中的 T 细胞记忆分化。IL-2 和 IL-7 刺激的强和弱 S6K（IL-2/S6K 和 IL-7/S6K）信号分别控制短暂的 IL-7RCD62LKLRG1 T 和长期的 IL-7RCD62LKLRG1 T 细胞形成。为了评估潜在的分子途径，我们使用 IL-7/S6K 刺激的 T（IL-7/T）和对照 IL-2/S6K 刺激的 T（IL-2/T）细胞进行流式细胞术、Western blot、共聚焦显微镜和 Seahorse 分析。我们确定 IL-7/S6K 信号在 IL-7/T 细胞中激活转录因子 FOXO1、TCF1 和 Id3 以及代谢物 p-AMPKα1、p-ULK1 和 ATG7。IL-7/T 细胞上调 IL-7R 和 CD62L，促进线粒体生物发生和脂肪酸氧化代谢，并显示长期的细胞存活和功能召回反应。有趣的是，AMPKα1 缺陷消除了 AMPKα1，但维持了 FOXO1 途径，并在 α KO IL-7/T 细胞中诱导从脂肪酸氧化到糖酵解的代谢转换，导致细胞存活和召回反应丧失。总之，我们的数据表明，IL-7 刺激的弱强度 mTORC1-S6K 信号通过激活转录因子 FOXO1-TCF1-Id3 和代谢物 AMPKα1-ULK1-ATG7 途径控制 T 细胞记忆。这（据我们所知）是一种新的发现，为 T 细胞记忆中的独特 IL-2/IL-7 刺激模型提供了一种新的机制，并极大地影响了疫苗的开发。
