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

Abstract

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.

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

“…In addition, we have shown that NTM exposure is an important factor in shaping the immune reactivity against MTB and that intragenus as well as intraspecies epitope conservation should be taken into account when investigating species-specific responses. Recent studies have shown that this conservation is important in diverse settings, such as human herpesviruses and grass pollen allergy (25,26). Chiu et al (26) showed that CD8 T cells responding to a varicella zoster virus epitope also respond to homologous epitopes derived from viruses as divergent as α-and γ-herpesviruses, independent of previous infection (26).…”

“…Recent studies have shown that this conservation is important in diverse settings, such as human herpesviruses and grass pollen allergy (25,26). Chiu et al (26) showed that CD8 T cells responding to a varicella zoster virus epitope also respond to homologous epitopes derived from viruses as divergent as α-and γ-herpesviruses, independent of previous infection (26). Similarly, Archila et al (25) showed that pollen-derived cross-reactive epitopes can be found in a wide variety of grass species.…”

Multiple Drug Hypersensitivity

“…Patients with a monoallergy did not have these CD4+ , CD25 dim , CD38+, and PD-1+ T cells [8]. Initially it was speculated that the continued CD38+ and PD-1+ expression within the CD4+, CD25 dim cell fraction might be due to an ongoing infection by endogenous herpes viruses, as the PD1+/CD38+ phenotype was also observed in chronic herpes virus infections [35,36]. However, a viral analysis of the patients failed to document an ongoing herpes virus (cytomegalovirus and HHV6) infection.…”

Vaccination and heterologous immunity: educating the immune system

“…Recent papers show high frequencies of virus-specific memory T cells in non-immune individuals and a crossreactive epitope spanning many types of herpes viruses. 40,47 Clear networks of crossreactive epitopes and patterns of beneficial or detrimental heterologous immunity have been defined in specific virus sequences in mouse models (Supplementary Figure 1). [24][25][26][27][28][29][30][31][32][33][34][48][49][50][51][52][53] For example, in the C57BL/6 mouse (H2 b ), CD8 T cell crossreactive epitopes have been defined between LCMV and Pichinde virus (PICV), LCMV and vaccinia virus (VACV), LCMV and murine cytomegalovirus (MCMV), LCMV and IAV, IAV and MCMV, and PICV and VACV, and complex networks of mouse or human T cell crossreactivity can exist between two viruses.…”