Broadly Reactive Human CD8 T Cells that Recognize an Epitope Conserved between VZV, HSV and EBV

PLoS Pathogens

Bjoern Peters¹  Mark Mulligan¹  John Sidney²  Megan McCausland³  Nadine Rouphael³  Bali Pulendran⁴  Nicole L. Sullivan⁴  Adriana Weinberg⁴  Aneesh Mehta⁵  Rafi Ahmed⁶  Fuh-Mei Duh⁶  Christopher Chiu⁶  Andreas Wieland⁷  Myron J. Levin⁷  Alessandro Sette⁸  Mary Carrington⁸ 

[1] Cancer and Inflammation Program, Laboratory for Experimental Immunology, SAIC Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America;Centre for Respiratory Infection, National Heart and Lung Institute, Imperial College London, London, United Kingdom;Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America;Division of Infectious Diseases School of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America;Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America;Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America;Hope Clinic of the Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America;Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America

关键词: T cells;    Cytotoxic T cells;    Herpesviruses;    Cytokines;    Phenotypes;    Vaccines;    Cell differentiation;    Lymphocytes;   

DOI  :  10.1371/journal.ppat.1004008

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 α-herpesviruses, HSV-1 and HSV-2, but also the γ-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.

【 授权许可】

CC BY