title: Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1.
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.
authors.affiliation: Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ruffo
authors.affiliation: Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Malacarne
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Sasha E
authors.initials: SE
authors.lastname: Larsen
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Rupali
authors.initials: R
authors.lastname: Das
authors.affiliation: Department of Life Sciences, University of Siena, 53100 Siena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Patrussi
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, BS8 1TH Bristol, UK.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wülfing
authors.affiliation: Biomolecular Photonics Group, Jena University Hospital, D 07740 Jena, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Biskup
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Senta M
authors.initials: SM
authors.lastname: Kapnick
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Verbist
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Paige
authors.initials: P
authors.lastname: Tedrick
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
authors.affiliation: Department of Life Sciences, University of Siena, 53100 Siena, Italy.
authors.forename: Cosima T
authors.initials: CT
authors.lastname: Baldari
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care and Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, D-07745 Jena, Germany.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Rubio
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Nichols
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Snow
authors.affiliation: Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Baldanzi
authors.affiliation: Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy. School of Medicine, University Vita e Salute San Raffaele, 20132 Milan, Italy. graziani.andrea@hsr.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Graziani
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D054992:Immunological Synapses / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008232:Lymphoproliferative Disorders / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011744:Pyrimidinones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein / Q000172:deficiency / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism
chemical_list: D016207:Cytokines; D026901:Membrane Transport Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C479458:OSCP1 protein, human; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013844:Thiazoles; C047505:R 59022; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D018631:ras Proteins