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

Sci Transl Med. 2016 Jan 13;8(321):321ra7. doi: 10.1126/scitranslmed.aad1565.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Death / drug effects
  • Cytokines / biosynthesis
  • Diacylglycerol Kinase / antagonists & inhibitors*
  • Diacylglycerol Kinase / metabolism
  • Gene Silencing / drug effects
  • Humans
  • Immunological Synapses / drug effects
  • Immunological Synapses / metabolism
  • Lymphocyte Activation
  • Lymphocyte Count
  • Lymphoproliferative Disorders / drug therapy
  • Lymphoproliferative Disorders / immunology*
  • Lymphoproliferative Disorders / pathology*
  • Membrane Transport Proteins / metabolism
  • Mice
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
  • Protein Kinase C / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrimidinones / pharmacology
  • Signal Transduction / drug effects
  • Signaling Lymphocytic Activation Molecule Associated Protein / deficiency
  • Signaling Lymphocytic Activation Molecule Associated Protein / metabolism
  • Thiazoles / pharmacology
  • ras Proteins / metabolism

Substances

  • Cytokines
  • Membrane Transport Proteins
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • OSCP1 protein, human
  • Protein Kinase Inhibitors
  • Pyrimidinones
  • Sh2d1a protein, mouse
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Thiazoles
  • R 59022
  • Diacylglycerol Kinase
  • Protein Kinase C
  • ras Proteins