National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA; Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.
Cell Rep. 2021 Oct 12;37(2):109804. doi: 10.1016/j.celrep.2021.109804.
Patients with activated phosphatidylinositol 3-kinase delta (PI3Kδ) syndrome (APDS) present with sinopulmonary infections, lymphadenopathy, and cytomegalvirus (CMV) and/or Epstein-Barr virus (EBV) viremia, yet why patients fail to clear certain chronic viral infections remains incompletely understood. Using patient samples and a mouse model (Pik3cd mice), we demonstrate that, upon activation, Pik3cd CD8 T cells exhibit exaggerated features of effector populations both in vitro and after viral infection that are associated with increased Fas-mediated apoptosis due to sustained FoxO1 phosphorylation and Fasl derepression, enhanced mTORC1 and c-Myc signatures, metabolic perturbations, and an altered chromatin landscape. Conversely, Pik3cd CD8 cells fail to sustain expression of proteins critical for central memory, including TCF1. Strikingly, activated Pik3cd CD8 cells exhibit altered transcriptional and epigenetic circuits characterized by pronounced interleukin-2 (IL-2)/STAT5 signatures and heightened IL-2 responses that prevent differentiation to memory-like cells in IL-15. Our data position PI3Kδ as integrating multiple signaling nodes that promote CD8 T cell effector differentiation, providing insight into phenotypes of patients with APDS.
患有活化磷脂酰肌醇 3-激酶 δ（PI3Kδ）综合征（APDS）的患者表现为鼻咽喉感染、淋巴结病以及巨细胞病毒（CMV）和/或EB 病毒（EBV）病毒血症，但为什么患者无法清除某些慢性病毒感染仍不完全清楚。我们使用患者样本和小鼠模型（Pik3cd 小鼠）证明，在激活后，Pik3cd CD8 T 细胞在体外和病毒感染后表现出效应细胞群体的过度特征，这与由于持续的 FoxO1 磷酸化和 FasL 去抑制导致的 Fas 介导的凋亡增加、增强的 mTORC1 和 c-Myc 特征、代谢紊乱以及改变的染色质景观有关。相反，Pik3cd CD8 细胞无法持续表达中央记忆所必需的蛋白质，包括 TCF1。引人注目的是，活化的 Pik3cd CD8 细胞表现出改变的转录和表观遗传回路，其特征是明显的白细胞介素 2（IL-2）/STAT5 特征和增强的 IL-2 反应，这阻止了在 IL-15 中向记忆样细胞分化。我们的数据将 PI3Kδ 定位为整合了多个促进 CD8 T 细胞效应分化的信号节点，为 APDS 患者的表型提供了深入了解。
