Differential Targeting and Shifts in the Immunodominance of Epstein‐Barr Virus–Specific CD8 and CD4 T Cell Responses during Acute and Persistent Infection

Woodberry, Tonia; Suscovich, Todd J.; Henry, Leah M.; Davis, Jennifer; Frahm, Nicole; Walker, Bruce D.; Scadden, David T.; Wang, Frederick; Berthou, Christian

doi:10.1086/491741

Cited by 71 publications

(72 citation statements)

References 52 publications

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“…Later studies on the prevalence of BZLF1-specific responses in persistent EBV infection have focused on recognition of these two epitopes. Epitope-specific responses were detected in 100% (6 of 6) of HLA-B8-positive individuals in two studies (11,32) and in 50% (5 of 10) of HLA-Cw6 individuals (32). Studies that address whether BZLF1-specific responses are prevalent in a larger, more diverse HLA population are limited.…”

Section: Discussionmentioning

confidence: 98%

The BZLF1 Homolog of an Epstein-Barr-Related γ-Herpesvirus Is a Frequent Target of the CTL Response in Persistently Infected Rhesus Macaques

Fogg

Garry

Awad

et al. 2006

The Journal of Immunology

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Although CD8+ T lymphocytes targeting lytic infection proteins dominate the immune response to acute and persistent EBV infection, their role in immune control of EBV replication is not known. Rhesus lymphocryptovirus (rhLCV) is a γ-herpesvirus closely related to EBV, which establishes persistent infection in rhesus macaques. In this study, we investigated cellular immune responses to the rhLCV BZLF1 (rhBZLF1) homolog in a cohort of rhLCV-seropositive rhesus macaques. rhBZLF1-specific IFN-γ ELISPOT responses ranging between 56 and 3070 spot-forming cells/106 PBMC were detected in 36 of 57 (63%) rhesus macaques and were largely mediated by CD8+ T lymphocytes. The prevalence and magnitude of ELISPOT responses were greater in adult (5–15 years of age) rather than juvenile macaques (<5 years of age), suggesting that rhBZLF1-specific CTL increase over time following early primary infection. A highly immunogenic region in the carboxyl terminus of the rhBZLF1 protein containing overlapping CTL epitopes restricted by Mamu-A*01 and other as yet unidentified MHC class I alleles was identified. The presence of a robust CD8+ T lymphocyte response targeting this lytic infection protein in both rhesus macaques and humans suggests that these CTL may be important for immune control of EBV-related γ-herpesvirus infection. These data underscore the utility of the rhLCV-macaque model for studies of EBV pathogenesis.

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Section: Discussionmentioning

confidence: 98%

The BZLF1 Homolog of an Epstein-Barr-Related γ-Herpesvirus Is a Frequent Target of the CTL Response in Persistently Infected Rhesus Macaques

Fogg

Garry

Awad

et al. 2006

The Journal of Immunology

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“…First, the recruitment of new clonotypes could be explained by temporal changes in epitope targeting. Such shifts in immunodominance and Ag recognition profile have been documented, albeit primarily for CD8 ϩ T cell responses, in several systems (33)(34)(35)(36)(37)(38)(39)(40)(41). Mechanistically, these changes can reflect differential Ag presentation (38), clonal exhaustion (39), and mutational escape from initially targeted epitopes (41) among other phenomena.…”

Section: Discussionmentioning

confidence: 99%

Induction and Evolution of Cytomegalovirus-Specific CD4+ T Cell Clonotypes in Rhesus Macaques

Price

Bitmansour

Edgar

et al. 2008

The Journal of Immunology

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CMV infection induces robust CD4+ T cell responses in immunocompetent hosts that orchestrate immune control of viral replication, dissemination, and disease. In this study, we characterized the clonotypic composition of CD4+ T cell populations specific for rhesus CMV (RhCMV) in chronically infected adult rhesus macaques (RM) and in juvenile RM undergoing primary RhCMV infection and subsequent secondary challenge with RhCMV. In adult RM with established chronic infection, RhCMV-specific CD4+ T cell populations exhibited stable, pauciclonal structures with skewed hierarchies dominated by two or three clonotypes. During primary infection, in contrast, the initial RhCMV-specific CD4+ T cell populations were highly polyclonal and progressive evolution to the chronic pattern manifest in adults occurred over the ensuing 2–3 years. Clear patterns of clonal succession were observed during this maturation process, such that clonotypes present in the acute phase were largely replaced over time. However, rechallenge with RhCMV expanded virus-specific CD4+ T cell clonotypes identified solely during acute infection. These findings indicate that, during persistent viral infection, substantial selection pressures and ongoing clonotype recruitment shape the specific CD4+ T cell repertoire and that rapidly exhausted or superseded clonotypes often remain within the memory T cell pool.

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“…After acute EBV infection, a large CD8 + T cell response is elicited which contracts subsequently into a smaller memory pool 57, 58, 59. Interestingly, it is known that at least one HLA‐A*02‐restricted lytic epitope reactivity present in the acute phase consistently disappears once infection resolves 57.…”

Section: Discussionmentioning

confidence: 99%

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Jones

Wockner

Brennan

et al. 2015

Clinical and Experimental Immunology

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SummaryIn 40% of cases of classical Hodgkin lymphoma (cHL), Epstein–Barr virus (EBV) latency‐II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV+cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA‐A*02 is protective in EBV+cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA‐A*02– versus HLA‐A*02+ EBV+cHL patients, suggesting that LMP2A‐specific CD8+ T cell anti‐tumoral immunity may be relatively ineffective in HLA‐A*02– EBV+cHL. To ascertain the impact of HLA class I on EBV latency antigen‐specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV+cHL, the magnitude of ex‐vivo LMP1/2A‐specific CD8+ T cell responses was elevated in HLA‐A*02+ patients. Furthermore, in a controlled in‐vitro assay, LMP2A‐specific CD8+ T cells from healthy HLA‐A*02 heterozygotes expanded to a greater extent with HLA‐A*02‐restricted compared to non‐HLA‐A*02‐restricted cell lines. In an extensive analysis of HLA class I‐restricted immunity, immunodominant EBNA3A/3B/3C‐specific CD8+ T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A‐specific responses were confined largely to HLA‐A*02. Our results demonstrate that HLA‐A*02 mediates a modest, but none the less stronger, EBV‐specific CD8+ T cell response than non‐HLA‐A*02 alleles, an effect confined to EBV latency‐II antigens. Thus, the protective effect of HLA‐A*02 against EBV+cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency‐II antigen‐specific CD8+ T cell hierarchies.

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Differential Targeting and Shifts in the Immunodominance of Epstein‐Barr Virus–Specific CD8 and CD4 T Cell Responses during Acute and Persistent Infection

Cited by 71 publications

References 52 publications

The BZLF1 Homolog of an Epstein-Barr-Related γ-Herpesvirus Is a Frequent Target of the CTL Response in Persistently Infected Rhesus Macaques

The BZLF1 Homolog of an Epstein-Barr-Related γ-Herpesvirus Is a Frequent Target of the CTL Response in Persistently Infected Rhesus Macaques

Induction and Evolution of Cytomegalovirus-Specific CD4+ T Cell Clonotypes in Rhesus Macaques

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

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