Department of Oncology, University of Lausanne, Lausanne, Switzerland.
Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
Sci Immunol. 2024 Aug 23;9(98):eadn2717. doi: 10.1126/sciimmunol.adn2717.
The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8 T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity.
记忆 T 细胞的形成是适应性免疫的一个基本特征，使机体能够建立针对病原体的长期保护。虽然有新的证据表明代谢重编程对于记忆 T 细胞的分化和存活至关重要，但驱动记忆 T 细胞代谢重编程的潜在机制仍不清楚。在这里，我们发现核受体过氧化物酶体增殖物激活受体 β/δ（PPARβ/δ）的上调指导了中央记忆 CD8 T 细胞建立过程中的代谢重编程。PPARβ/δ 调节的变化包括抑制有氧糖酵解和增强氧化代谢和脂肪酸氧化。在机制上，白细胞介素 15 的暴露和 T 细胞因子 1 的表达促进了 PPARβ/δ 途径的激活，抵消了抗原清除和代谢应激诱导的细胞凋亡。总之，我们的研究结果表明，PPARβ/δ 是协调代谢转换的主要代谢调节剂，这种代谢转换可能有利于 T 细胞的长寿。
