Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA; and.
J Immunol. 2022 Dec 15;209(12):2287-2291. doi: 10.4049/jimmunol.2100669.
The mechanistic target of rapamycin is an essential regulator of T cell metabolism and differentiation. In this study, we demonstrate that serum- and glucocorticoid-regulated kinase 1 (SGK1), a downstream node of mechanistic target of rapamycin complex 2 signaling, represses memory CD8+ T cell differentiation. During acute infections, murine SGK1-deficient CD8+ T cells adopt an early memory precursor phenotype leading to more long-lived memory T cells. Thus, SGK1-deficient CD8+ T cells demonstrate an enhanced recall capacity in response to reinfection and can readily reject tumors. Mechanistically, activation of SGK1-deficient CD8+ T cells results in decreased Foxo1 phosphorylation and increased nuclear translocation of Foxo1 to promote early memory development. Overall, SGK1 might prove to be a powerful target for enhancing the efficacy of vaccines and tumor immunotherapy.
雷帕霉素的作用靶点是 T 细胞代谢和分化的必需调节因子。在这项研究中，我们证明了血清和糖皮质激素调节激酶 1（SGK1），雷帕霉素复合物 2 信号的下游节点，抑制记忆 CD8+T 细胞分化。在急性感染期间，鼠 SGK1 缺陷型 CD8+T 细胞表现出早期记忆前体细胞表型，导致更持久的记忆 T 细胞。因此，SGK1 缺陷型 CD8+T 细胞在再次感染时表现出增强的回忆能力，并且可以轻易地排斥肿瘤。从机制上讲，SGK1 缺陷型 CD8+T 细胞的激活导致 Foxo1 磷酸化减少和 Foxo1 的核易位增加，从而促进早期记忆的发展。总的来说，SGK1 可能被证明是增强疫苗和肿瘤免疫治疗效果的有效靶点。
