Differential Evolution and Stability of Epitope-Specific CD8+ T Cell Responses in EBV Infection

Abstract

Murine models of lymphocytic choriomeningitis virus infection suggest that the memory CD8+ T cell repertoire is reflective of the CD8+ T cell repertoire generated during acute infection. Less is known regarding the evolution of CD8+ T cell repertoires during human viral infections. We therefore examined epitope-specific CD8+ T cell responses in a large cohort of individuals with acute through latent Epstein-Barr virus infection. Using 16 of 20 published EBV epitopes restricted by HLA-A2, HLA-A3 or HLA-B7, we showed that lytic cycle-specific CD8+ T cell responses predominated during acute EBV infection. However, whereas HLA-A2+-restricted BMLF-1-specific CD8+ T cell responses were maintained through latency, HLA-A2+- and HLA-B7+-restricted BZLF-1, as well as HLA-A3+-restricted BRLF-1 CD8+ T cell responses, were generated but not readily maintained. Analyses of CD8+ T cell responses to EBV latent cycle Ags showed delayed detection and lower frequencies of latent epitope-specific CD8+ T cell responses during acute EBV infection, with maintenance of these responses 1 yr post-EBV infection. Early BMLF-1 and EBNA-3A epitope-specific CD8+ T cell frequencies did not correlate with their frequencies at 1 yr postinfection. Interestingly, populations of EBV-specific CD8+ T cells were stable during 20 mo in our long term EBV-seropositive populations, suggesting homeostasis between virus and the host immune system. This study demonstrates that CD8+ T cell repertoires generated during persistent viral infections are not simply reflective of the initial pool of CD8+ T cells and provides evidence that the generation of CD8+ T cell responses to a persistent infection is a dynamic process.

Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection

“…ELISPOT assay and tetramer staining identify virus-specific CD8 ϩ T cells directly ex vivo and therefore may more accurately reflect CD8 ϩ T cell specificities in vivo. Finally, the protein specificity of HCMV-specific CD8 ϩ T cell responses may depend on HLA type (52,60,61). In our study all infants with responses to pp65 alone were HLA-A2 ϩ , whereas only one-third of those with responses to both gene products were HLA-A2 ϩ .…”

“…We and others have previously shown phenotypic and functional heterogeneity of virus-specific CD8 ϩ T cell populations over the course of viral infections (52,54). Tetramer staining is a method that quantifies epitope-specific T cells without regard to functional activity; thus, virus-specific T cell frequencies detected by tetramer staining are commonly higher than those detected by other methods.…”

“…Differential CD8 ϩ T cell recognition of viral protein epitopes has been described from acute through chronic EBV (52) and HIV-1 (53) infection. We therefore began to study the pp65 and IE1 epitope specificities of HCMV-specific CD8 ϩ T cell responses in children with congenital or postnatal HCMV infection.…”

Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells

“…Thus, it seems that the determination of IE-and pp65-specific CD8 + T cells may in some cases underestimate the real efficiency of the immune system against HCMV infection. In this respect, it seems important to recall that changes in the protein and epitope specificity of HCMVspecific CD8 + T cells over time have been reported in children with congenital or postnatal HCMV infection [18] as well as during Epstein-Barr virus infection [19]. This might be due to different viral antigen processing and presentation [20].…”

Monocyte-Derived Dendritic Cells Generated After a Short-Term Culture with IFN-α and Granulocyte-Macrophage Colony-Stimulating Factor Stimulate a Potent Epstein-Barr Virus-Specific CD8+ T Cell Response

“…In fact, whereas similar high frequencies of T cells reactive to the BMLF-1 (GLC) epitope were obtained using IFN-DCs or IL-4-DCs as stimulators, the expansion of T cells specific for the gp350 epitope was promoted exclusively by IFNDCs. Several studies have demonstrated that responses to lytic cycle Ags, including BMLF-1, are detectable in CTL memory (21,30,31) and can dominate those to latent cycle Ags (32), as in the case of donor LL, whose basal frequency of T cells reactive against the BMLF-1 (GLC) epitope largely exceeded that of each latent cycle Ag reactivity tested. Moreover, BMLF-1 (GLC) epitope-specific T cells can be easily detected in sensitive ELISPOT assays by adding the corresponding peptide to total PBMCs as responders (30,32), indicating that relatively inefficient APCs, such as the IL-4-DCs used in this study, can stimulate T cells reactive to this immunodominant epitope.…”