Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1

Elisa Ruffo, Valeria Malarcance, Sasha Larsen, Rupali Das, Laura Patrussi, Christoph Wülfing, Christoph Biskup, Senta Kapnick, Katherine Verbist, Paige Tedrick, Pamela Schwartzberg, Cosima Baldari, Ignacio Rubio, Kim Nichols, Andrew Snow, Gianluca Baldanzi, Andrea Graziani

Research output: Contribution to journalArticle (Academic Journal)

20 Citations (Scopus)

Abstract

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.
Original languageEnglish
Article number321ra7
JournalScience Translational Medicine
Volume8
Issue number321
DOIs
Publication statusPublished - 13 Jan 2016

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    Ruffo, E., Malarcance, V., Larsen, S., Das, R., Patrussi, L., Wülfing, C., Biskup, C., Kapnick, S., Verbist, K., Tedrick, P., Schwartzberg, P., Baldari, C., Rubio, I., Nichols, K., Snow, A., Baldanzi, G., & Graziani, A. (2016). Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1. Science Translational Medicine, 8(321), [321ra7]. https://doi.org/10.1126/scitranslmed.aad1565