Reactive Human CD 8 T Cells that Recognize an Epitope Conserved between VZV , HSV and EBV

Human herpesviruses are important causes of potentially severe chronic infections for which T cells are believed to be necessary for control. In order to examine the role of virus-specific CD8 T cells against Varicella Zoster Virus (VZV), we generated a comprehensive panel of potential epitopes predicted in silico and screened for T cell responses in healthy VZV seropositive donors. We identified a dominant HLA-A*0201-restricted epitope in the VZV ribonucleotide reductase subunit 2 and used a tetramer to analyze the phenotype and function of epitope-specific CD8 T cells. Interestingly, CD8 T cells responding to this VZV epitope also recognized homologous epitopes, not only in the other a-herpesviruses, HSV-1 and HSV-2, but also the c-herpesvirus, EBV. Responses against these epitopes did not depend on previous infection with the originating virus, thus indicating the cross-reactive nature of this T cell population. Between individuals, the cells demonstrated marked phenotypic heterogeneity. This was associated with differences in functional capacity related to increased inhibitory receptor expression (including PD-1) along with decreased expression of co-stimulatory molecules that potentially reflected their stimulation history. Vaccination with the live attenuated Zostavax vaccine did not efficiently stimulate a proliferative response in this epitope-specific population. Thus, we identified a human CD8 T cell epitope that is conserved in four clinically important herpesviruses but that was poorly boosted by the current adult VZV vaccine. We discuss the concept of a ‘‘pan-herpesvirus’’ vaccine that this discovery raises and the hurdles that may need to be overcome in order to achieve this. Citation: Chiu C, McCausland M, Sidney J, Duh F-M, Rouphael N, et al. (2014) Broadly Reactive Human CD8 T Cells that Recognize an Epitope Conserved between VZV, HSV and EBV. PLoS Pathog 10(3): e1004008. doi:10.1371/journal.ppat.1004008 Editor: Frank Carbone, University of Melbourne, Australia Received June 20, 2013; Accepted February 3, 2014; Published March 27, 2014 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This work was in part funded by NIH/NIAID U19-A1057266, NIH/NIAID U19-A1090023-01 (RA), Cooperative Centers for Translational Research on Human Immunology and Biodefense (CCHI) grant U19-AI05726, with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E, and by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. CC is funded by the Medical Research Council, UK (G0902266). NLS was supported by the Irvington Institute Fellowship Program of the Cancer Research Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: c.chiu@imperial.ac.uk (CC); rahmed@emory.edu (RA)