Institut Toulousain des Maladies Infectieuses et Inflammatoires, Institut National de la Santé et de la Recherche Médicale UMR1291, Centre National de la Recherche Scientifique UMR5051, Université Toulouse III , Toulouse, France.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
J Exp Med. 2024 Feb 5;221(2). doi: 10.1084/jem.20230449. Epub 2024 Jan 8.
The mechanisms whereby Eomes controls tissue accumulation of T cells and strengthens inflammation remain ill-defined. Here, we show that Eomes deletion in antigen-specific CD4+ T cells is sufficient to protect against central nervous system (CNS) inflammation. While Eomes is dispensable for the initial priming of CD4+ T cells, it is required for long-term maintenance of CNS-infiltrating CD4+ T cells. We reveal that the impact of Eomes on effector CD4+ T cell longevity is associated with sustained expression of multiple genes involved in mitochondrial organization and functions. Accordingly, epigenetic studies demonstrate that Eomes supports mitochondrial function by direct binding to either metabolism-associated genes or mitochondrial transcriptional modulators. Besides, the significance of these findings was confirmed in CD4+ T cells from healthy donors and multiple sclerosis patients. Together, our data reveal a new mechanism by which Eomes promotes severity and chronicity of inflammation via the enhancement of CD4+ T cell mitochondrial functions and resistance to stress-induced cell death.
Eomes 控制 T 细胞组织积累并增强炎症的机制仍不清楚。在这里，我们表明抗原特异性 CD4+T 细胞中 Eomes 的缺失足以防止中枢神经系统 (CNS) 炎症。虽然 Eomes 对于 CD4+T 细胞的初始启动是可有可无的，但它对于 CNS 浸润的 CD4+T 细胞的长期维持是必需的。我们揭示了 Eomes 对效应 CD4+T 细胞寿命的影响与多个涉及线粒体组织和功能的基因的持续表达有关。因此，表观遗传学研究表明，Eomes 通过直接结合代谢相关基因或线粒体转录调节剂来支持线粒体功能。此外，这些发现的意义在来自健康供体和多发性硬化症患者的 CD4+T 细胞中得到了证实。总之，我们的数据揭示了一种新的机制，即 Eomes 通过增强 CD4+T 细胞的线粒体功能和对应激诱导的细胞死亡的抵抗力，促进炎症的严重程度和慢性化。
