SAP-mediated inhibition of Diacylglycerol kinase alpha regulates TCR-induced diacylglycerol signaling and restimulation induced cell death in XLP patients

Abstract

Event Abstract Back to Event SAP-mediated inhibition of Diacylglycerol kinase alpha regulates TCR-induced diacylglycerol signaling and restimulation induced cell death in XLP patients Valeria Malacarne1*, Gianluca Baldanzi1, Andrea Graziani1, Elisa Ruffo1, Andrew Snow2, Cosima T. Baldari3 and Laura Patrussi3 1 Università del Piemonte Orientale "A. Avogadro" - Dipartimento Medicina Traslazionale, Italy 2 Uniformed Services University of the Health Sciences, Dept of Pharmacology, C2013, United States 3 University of Siena, Italy X-linked lymphoproliferative disease (XLP) is a rare congenital immunodeficiency leading to a usually fatal lymphocytosis following EBV infection. It is characterized by loss of expression of SLAM-associated protein (SAP), which results in defective SLAM family receptors and TCR signaling. Recent evidences showed that SAP deficiency causes resistance to TCR re-stimulation induced cell death (RICD), a process that physiologically constrains T cell expansion during immune responses (Snow, JCI 2009). We recently showed that, upon TCR stimulation, SAP mediates negative regulation of the enzymatic activity of Diacylglycerol kinase alpha (DGKα) (Baldanzi, J. Immunol. 2011). DGKα, phosphorylating diacylglcyerol to phosphatidic acid, is a well-known negative regulator of TCR signaling. In SAP-deficient Jurkat cells, inhibition of DGKα partially rescues defective TCR/CD28 signaling, including Ras and ERK-1/2 activation, PKCθ membrane recruitment, induction of NF-AT transcriptional activity and IL-2 production. Here we show that both DGKα silencing and pharmacological inhibition restore diacylglycerol signaling in SAP deficient primary T cells, thereby enhancing T cell activation (ERK phosphorylation and cytokines production). Moreover, DGKα knockdown efficiently restores FASL and BIM expression, reestablishing TCR-induced apoptosis of SAP deficient cells. Intriguingly, DGKα silencing/inhibition fully restore RICD in SAP knockdown T cells, as well as in T cells from XLP patients. Thus, DGKα inhibition is sufficient to correct the defective TCR signaling and RICD in SAP defective cells ex-vivo, indicating a key role of the SAP-DGKα pathway in RICD control. These data also suggest that DGKα inhibition could be a novel pharmacological strategy for treatment of XLP and others lymphoproliferative diseases. References Baldanzi, G. et al. SAP-mediated inhibition of diacylglycerol kinase a regulates TCR-induced diacylglycerol signaling. J Immunol 187, 5941-5951, doi:jimmunol.1002476 [pii] (2011). Snow, A. L. et al. Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. J Clin Invest 119, 2976-2989, doi:39518 [pii] (2009). Keywords: T-Lymphocytes, X-Linked Lymphoproliferative Disorder, T-cell receptor, Diacylglycerol Kinase, SLAM-associated protein Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune receptors and signaling Citation: Malacarne V, Baldanzi G, Graziani A, Ruffo E, Snow A, Baldari CT and Patrussi L (2013). SAP-mediated inhibition of Diacylglycerol kinase alpha regulates TCR-induced diacylglycerol signaling and restimulation induced cell death in XLP patients. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.01150 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 31 Jul 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Valeria Malacarne, Università del Piemonte Orientale "A. Avogadro" - Dipartimento Medicina Traslazionale, Novara, Italy, valeria.malacarne@med.uniupo.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Valeria Malacarne Gianluca Baldanzi Andrea Graziani Elisa Ruffo Andrew Snow Cosima T Baldari Laura Patrussi Google Valeria Malacarne Gianluca Baldanzi Andrea Graziani Elisa Ruffo Andrew Snow Cosima T Baldari Laura Patrussi Google Scholar Valeria Malacarne Gianluca Baldanzi Andrea Graziani Elisa Ruffo Andrew Snow Cosima T Baldari Laura Patrussi PubMed Valeria Malacarne Gianluca Baldanzi Andrea Graziani Elisa Ruffo Andrew Snow Cosima T Baldari Laura Patrussi Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.