Ruffo Elisa, Malacarne Valeria, Larsen Sasha E, Das Rupali, Patrussi Laura, Wülfing Christoph, Biskup Christoph, Kapnick Senta M, Verbist Katherine, Tedrick Paige, Schwartzberg Pamela L, Baldari Cosima T, Rubio Ignacio, Nichols Kim E, Snow Andrew L, Baldanzi Gianluca, Graziani Andrea
Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Sci Transl Med. 2016 Jan 13;8(321):321ra7. doi: 10.1126/scitranslmed.aad1565.
X-linked lymphoproliferative disease (XLP-1) is an often-fatal primary immunodeficiency associated with the exuberant expansion of activated CD8(+) T cells after Epstein-Barr virus (EBV) infection. XLP-1 is caused by defects in signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), an adaptor protein that modulates T cell receptor (TCR)-induced signaling. SAP-deficient T cells exhibit impaired TCR restimulation-induced cell death (RICD) and diminished TCR-induced inhibition of diacylglycerol kinase α (DGKα), leading to increased diacylglycerol metabolism and decreased signaling through Ras and PKCθ (protein kinase Cθ). We show that down-regulation of DGKα activity in SAP-deficient T cells restores diacylglycerol signaling at the immune synapse and rescues RICD via induction of the proapoptotic proteins NUR77 and NOR1. Pharmacological inhibition of DGKα prevents the excessive CD8(+) T cell expansion and interferon-γ production that occur in SAP-deficient mice after lymphocytic choriomeningitis virus infection without impairing lytic activity. Collectively, these data highlight DGKα as a viable therapeutic target to reverse the life-threatening EBV-associated immunopathology that occurs in XLP-1 patients.
X连锁淋巴增生性疾病（XLP-1）是一种常致命的原发性免疫缺陷病，与感染爱泼斯坦-巴尔病毒（EBV）后活化的CD8(+) T细胞过度增殖有关。XLP-1由信号淋巴细胞激活分子（SLAM）相关蛋白（SAP）缺陷引起，SAP是一种调节T细胞受体（TCR）诱导信号传导的衔接蛋白。缺乏SAP的T细胞表现出TCR再刺激诱导的细胞死亡（RICD）受损，以及TCR诱导的二酰基甘油激酶α（DGKα）抑制作用减弱，导致二酰基甘油代谢增加，通过Ras和蛋白激酶Cθ（PKCθ）的信号传导减少。我们发现，在缺乏SAP的T细胞中下调DGKα活性可恢复免疫突触处的二酰基甘油信号传导，并通过诱导促凋亡蛋白NUR77和NOR1挽救RICD。对DGKα的药理学抑制可防止淋巴细胞性脉络丛脑膜炎病毒感染后缺乏SAP的小鼠中发生的过度CD8(+) T细胞扩增和干扰素-γ产生，而不损害裂解活性。总体而言，这些数据突出了DGKα作为一个可行的治疗靶点，以逆转XLP-1患者中发生的危及生命的EBV相关免疫病理。
