Vaccine Activation of the Nutrient Sensor GCN2 in Dendritic Cells Enhances Antigen Presentation

• Type of Material: Article
• Authors: Rajesh Ravindran, Emory University; Nooruddin Khan, Emory University; Helder Nakaya, Emory University; Shuzhao Li, Emory University; Jens Loebbermann, Emory University; Mohan S. Maddur, Emory University; Youngja Park, Emory University; Dean P Jones, Emory University; Pascal Chappert, Université Paris Descartes; Jean Davoust, Université Paris Descartes; David S Weiss, Emory University; Herbert W. Virgin, Washington University; David Ron, University of Cambridge; Bali Pulendran, Emory University
• Language: English
• Date: 2014-01-17
• Publisher: Volgogradskii Gosudarstvennyi Universitet (Volgograd State University)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright 2014 by the American Association for the Advancement of Science; all rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1126/science.1246829
• Title of Journal or Parent Work: Вестник Волгоградского государственног... / Science Journal of Volgograd State University. History. Area Studies. International Relations
• ISSN: 1998-9938
• Volume: 343
• Issue: 6168
• Start Page: 313
• End Page: 317
• Grant/Funding Information: This work was supported by grants from the U.S. National Institutes of Health (grants R37 DK057665, R37 AI048638, U19 AI090023, U19 AI057266, U54 AI057157, N01 AI50019, and N01 AI50025) and from the Bill & Melinda Gates Foundation to B.P., a Wellcome Trust Principal Research Fellowship (084812/Z/08/Z) to D.R, and NIH grant U54 AI057160 to H.W.V.
• Keywords: Science & Technology - Other Topics; Science & Technology; RNA; Multidisciplinary Sciences; AUTOPHAGY; INITIATION-FACTOR 2-ALPHA; YELLOW-FEVER VACCINE; STRESS; PHOSPHORYLATION; TRANSLATIONAL CONTROL; KINASE; CD8(+) T-CELLS; MICE
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology

Abstract

The yellow fever vaccine YF-17D is one of the most successful vaccines ever developed in humans. Despite its efficacy and widespread use in more than 600 million people, the mechanisms by which it stimulates protective immunity remain poorly understood. Recent studies using systems biology approaches in humans have revealed that YF-17D-induced early expression of general control nonderepressible 2 kinase (GCN2) in the blood strongly correlates with the magnitude of the later CD8+ T cell response. We demonstrate a key role for virus-induced GCN2 activation in programming dendritic cells to initiate autophagy and enhanced antigen presentation to both CD4+ and CD8+ T cells. These results reveal an unappreciated link between virus-induced integrated stress response in dendritic cells and the adaptive immune response.