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

Date Published: March 27, 2014

Publisher: Public Library of Science

Author(s): Christopher Chiu, Megan McCausland, John Sidney, Fuh-Mei Duh, Nadine Rouphael, Aneesh Mehta, Mark Mulligan, Mary Carrington, Andreas Wieland, Nicole L. Sullivan, Adriana Weinberg, Myron J. Levin, Bali Pulendran, Bjoern Peters, Alessandro Sette, Rafi Ahmed, Frank Carbone.


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.

Partial Text

The family Herpesviridae encompasses several highly prevalent human pathogens that cause a spectrum of diseases ranging from mildly symptomatic to severe life-threatening illness [1]. All herpesvirus subfamilies (α, β, and γ) share one important characteristic: the ability to evade the immune response while persisting as latent infections in a state of minimal gene transcription. In many individuals, latent herpesviruses cause no further disease. However, reactivations do occur that lead to considerable morbidity and mortality as well as promoting onward transmission. These events are most frequent in individuals with immunosuppression or immunosenescence [2]. However, asymptomatic reactivation can also occur in immunocompetent individuals, leading to recurrent stimulation of host immunity by herpesvirus antigens [3], [4]. T cells are essential both for recovery from primary herpesvirus infections and prevention of symptomatic reactivation [5]. VZV-specific T cells that secrete Th1 cytokines and exhibit cytolytic activity are detectable following chicken pox [6]. While virus exposure also induces antibodies, the absence of antibodies in children with agammaglobulinemia does not lead to more severe disease [7]. Conversely, the waning T cell immunity that occurs with older age is associated with greater frequency and severity of reactivations [8].

Several T cell epitopes have previously been described that are conserved between HSV-1 and HSV-2 [20], including the epitopes described here [21]. However, it is interesting to find that these conserved epitopes exist more widely in viruses as divergent as the α- and γ-herpesviruses. Here, we have shown that this epitope is, in fact, broadly conserved between 4 different clinically important herpesvirus species despite their sequence divergence. Furthermore, all epitopes were capable of stimulating CD8 T cells even in individuals with no evidence of previous exposure to that virus. Earlier studies have indeed noted that HSV-specific T cells are detectable in a proportion of individuals seronegative for HSV. It was then proposed that these T cells might be induced by subclinical infection or exposure without infection, but our findings suggest that cross-reactivity of T cells may be an alternative explanation [22].




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