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

Research output: Contribution to journalArticle

  • 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
Original languageEnglish
Article number321ra7
JournalScience Translational Medicine
Volume8
Issue number321
DOIs
DateAccepted/In press - 3 Dec 2015
DatePublished (current) - 13 Jan 2016

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.

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