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

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

doi:10.1126/scitranslmed.aad1565

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.

Authors

Elisa Ruffo¹, Valeria Malacarne¹, Sasha E Larsen², Rupali Das³, Laura Patrussi⁴, Christoph Wülfing⁵, Christoph Biskup⁶, Senta M Kapnick⁷, Katherine Verbist⁸, Paige Tedrick⁸, Pamela L Schwartzberg⁷, Cosima T Baldari⁴, Ignacio Rubio⁹, Kim E Nichols⁸, Andrew L Snow², Gianluca Baldanzi¹, Andrea Graziani¹⁰

Affiliations

¹ Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
² Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
³ Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
⁴ Department of Life Sciences, University of Siena, 53100 Siena, Italy.
⁵ School of Cellular and Molecular Medicine, University of Bristol, BS8 1TH Bristol, UK.
⁶ Biomolecular Photonics Group, Jena University Hospital, D 07740 Jena, Germany.
⁷ Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁹ 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.
¹⁰ 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. [email protected].

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding