CD8+ immunodominance among Epstein-Barr virus lytic cycle antigens directly reflects the efficiency of antigen presentation in lytically infected cells

Abstract

Antigen immunodominance is an unexplained feature of CD8+ T cell responses to herpesviruses, which are agents whose lytic replication involves the sequential expression of immediate early (IE), early (E), and late (L) proteins. Here, we analyze the primary CD8 response to Epstein-Barr virus (EBV) infection for reactivity to 2 IE proteins, 11 representative E proteins, and 10 representative L proteins, across a range of HLA backgrounds. Responses were consistently skewed toward epitopes in IE and a subset of E proteins, with only occasional responses to novel epitopes in L proteins. CD8+ T cell clones to representative IE, E, and L epitopes were assayed against EBV-transformed lymphoblastoid cell lines (LCLs) containing lytically infected cells. This showed direct recognition of lytically infected cells by all three sets of effectors but at markedly different levels, in the order IE > E ≫ L, indicating that the efficiency of epitope presentation falls dramatically with progress of the lytic cycle. Thus, EBV lytic cycle antigens display a hierarchy of immunodominance that directly reflects the efficiency of their presentation in lytically infected cells; the CD8+ T cell response thereby focuses on targets whose recognition leads to maximal biologic effect.

A Role for Intercellular Antigen Transfer in the Recognition of EBV-Transformed B Cell Lines by EBV Nuclear Antigen-Specific CD4+ T Cells

“…Indeed from recent work, this also seems to be true of exogenously acquired EBV lytic cycle Ags. Thus, coculture between appropriate mixtures of semipermissive HLAmismatched (donor) and nonpermissive HLA-matched (recipient) LCL never led to recognition by lytic epitope-specific CD8 ϩ T cells (53). By contrast, the recognition of semipermissive LCL cells by virus-structural Ag-specific CD4 ϩ T cells was found to be dependent upon the intercellular transfer of virions within the culture (54).…”

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

“…Strong CD8 ϩ T cell responses to the tegument phosphoprotein 65 and the immediate early protein 1 were found for the ␤-herpesvirus human CMV (24,25). In healthy carriers of the ␥-herpesvirus EBV, a considerable proportion of the peripheral T cell repertoire is directed against EBV-encoded Ags, predominantly derived from latent and immediate early viral proteins (26). Thus, despite the presence of a fully competent immune system mounting a powerful response against herpesvirus infections, these viruses fail to be eliminated.…”

CD4+ T-cell clones recognizing human lymphoma-associated antigens: generation by in vitro stimulation with autologous Epstein-Barr virus–transformed B cells

“…The latter responses can be numerically dominant and are directed, in the case of CD4 ϩ T cells, mainly against reprocessed virion structural proteins 21 and, in the case of CD8 ϩ T cells, mainly against immediate early and early nonstructural proteins. 34 Using LCLs transformed with a virus deleted for BZLF1, the key initiator of EBV lytic cycle, allows one to exclude lytic cycle proteins as an antigen source. As anticipated, we found that seropositive donors mounted ex vivo CD8 responses that were stronger to the wild-type than to the BZ k/o virus-transformed LCL, whereas seronegative donors responded to neither stimulus.…”