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Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1.
Ruffo, Elisa; Malacarne, Valeria; Larsen, Sasha E; Das, Rupali; Patrussi, Laura; Wülfing, Christoph; Biskup, Christoph; Kapnick, Senta M; Verbist, Katherine; Tedrick, Paige; Schwartzberg, Pamela L; Baldari, Cosima T; Rubio, Ignacio; Nichols, Kim E; Snow, Andrew L; Baldanzi, Gianluca; Graziani, Andrea.
Afiliación
  • Ruffo E; Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
  • Malacarne V; Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
  • Larsen SE; Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
  • Das R; Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
  • Patrussi L; Department of Life Sciences, University of Siena, 53100 Siena, Italy.
  • Wülfing C; School of Cellular and Molecular Medicine, University of Bristol, BS8 1TH Bristol, UK.
  • Biskup C; Biomolecular Photonics Group, Jena University Hospital, D 07740 Jena, Germany.
  • Kapnick SM; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Verbist K; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • Tedrick P; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • Schwartzberg PL; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Baldari CT; Department of Life Sciences, University of Siena, 53100 Siena, Italy.
  • Rubio I; 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.
  • Nichols KE; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • Snow AL; Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
  • Baldanzi G; Department of Translational Medicine and Institute for Research and Cure of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
  • Graziani A; 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.
Sci Transl Med ; 8(321): 321ra7, 2016 Jan 13.
Article en En | MEDLINE | ID: mdl-26764158
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diacilglicerol Quinasa / Trastornos Linfoproliferativos Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diacilglicerol Quinasa / Trastornos Linfoproliferativos Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos