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

Jones, Kimberley; Wockner, Leesa; Brennan, Rebekah; Keane, Colm; Chattopadhyay, Pratip K.; Price, David A.; Cole, David K.; Hassan, Brekhna; Beck, Konrad; Gottlieb, David; Ritchie, David; Seymour, John F.; Vari, Frank; Crooks, Pauline; Burrows, Scott R.; Gandhi, Maher K.

doi:10.1111/cei.12716

Cited by 39 publications

(36 citation statements)

References 68 publications

(111 reference statements)

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“…This contrasts sharply with EBV latent antigen-specific responses where examples of HLA-C restriction are extremely rare [8,37]. Finally, one of the more interesting comparisons between individual alleles involved HLA-A*0101 and A*0201 because of their identification as high and low risk alleles respectively for the development of EBV-positive Hodgkin lymphoma [38][39][40], a disease potentially linked to impaired T cell surveillance [39,41]. In that regard, previous studies have defined a small number of EBV latent and lytic epitopes restricted though A*0201, whereas numerous studies have failed to reveal any EBV-specific responses restricted through A*0101 [8,42].…”

Section: Discussionmentioning

confidence: 99%

Proteome-Wide Analysis of Cd8+ T Cell Responses to Ebv Reveals Differences Between Primary and Persistent Infection

Forrest

Hislop

Rickinson

et al. 2018

Preprint

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words)Human herpesviruses are antigenically rich agents that induce strong CD8+T cell responses in primary infection yet persist for life, continually challenging T cell memory through recurrent lytic replication and potentially influencing the spectrum of antigen-specific responses. Here we describe the first lytic proteome-wide analysis of CD8+ T cell responses to the Epstein-Barr gamma1-herpesvirus (EBV), and the first such proteome-wide analysis of primary versus memory CD8 responses to any human herpesvirus. Primary effector preparations were generated directly from activated CD8+ T cells in the blood of infectious mononucleosis (IM) patients by in vitro mitogenic expansion. For memory preparations, EBV-specific cells in the blood of long-term virus carriers were first re-stimulated in vitro by autologous dendritic cells loaded with a lysate of lytically-infected cells, then expanded as for IM cells. Preparations from 7 donors of each type were screened against each of 70 EBV lytic cycle proteins in combination with the donor's individual HLA class I alleles. Multiple reactivities against immediate early (IE), early (E) and late (L) lytic cycle proteins, including many hitherto unrecognised targets, were detected in both contexts. Interestingly however, the two donor cohorts showed a different balance between IE, E and L reactivities. Primary responses targeted IE and a small group of E proteins preferentially, seemingly in line with their better presentation on the infected cell surface before later-expressed viral evasins take full hold. By contrast, target choice equilibrates in virus carriage with responses to key IE and E antigens still present but with responses to a select subset of L proteins now often prominent. We infer that, for EBV at least, long-term virus carriage with its low level virus replication and lytic antigen release is associated with a re-shaping of the virus-specific response.3 Author Summary (156 words) Epstein-Barr virus (EBV) is a herpesvirus and an important human pathogen that normally persists for life and induces strong CD8+T cell responses. Primary EBV infection can cause mononucleosis (IM) disease and EBV is associated with malignant lymphocytes cancers and epithelial cells. Here for the first time, we described proteome-wide analysis of CD8+ T cell responses to EBV lytic antigens, and compare the CD8 T cell responses between primary and memory CD8 responses to EBV. The EBV primary CD8 T cells responses targeted IE and a small group of E proteins preferentially. By contrast, the memory CD8 T cells responses from EBV persistent infection are dominated by L proteins. This study can help to understand how human CD8 T cells respond evolves with the long-term virus infection. For EBV at least, we infer that long-term EBV virus carriage with its low level virus replication and lytic antigen release is associated with a re-shaping of the virus-specific response.4

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Section: Discussionmentioning

confidence: 99%

Proteome-Wide Analysis of Cd8+ T Cell Responses to Ebv Reveals Differences Between Primary and Persistent Infection

Forrest

Hislop

Rickinson

et al. 2018

Preprint

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“…The protective effect of the HLA-A*02:01 allele in Europeans could be explained by common anti-EBV immune responses to antigens that are specifically presented by A*02:01 encoded HLA [28]. At the moment, it is unknown how HLA-A*01:01 and HLA-A*02:07 exert a risk effect, although this can be partially explained by lack of EBV latency type II responses in the context of these alleles.…”

Section: Discussionmentioning

confidence: 99%

HLA expression and HLA type associations in relation to EBV status in Hispanic Hodgkin lymphoma patients

et al. 2017

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A proportion of classical Hodgkin lymphomas harbor the Epstein Barr virus (EBV). We previously demonstrated that associations between Human Leukocyte Antigen (HLA) alleles and susceptibility to EBV+ classical Hodgkin lymphoma differ between European and Chinese populations. Data on Hispanic populations is missing. Here we examined the association between HLA type, tumor cell HLA expression and other characteristics in Hispanic Hodgkin lymphoma patients. Hispanic Hodgkin lymphoma patients diagnosed at the Los Angeles County-University of Southern California Medical Center from 2000–2012 were included (n = 65). Formalin-fixed paraffin-embedded tumor tissue was analyzed for EBV by in situ hybridization and for HLA class I and class II expression by immunohistochemistry. HLA typing was performed by HLA-A specific quantitative PCR of genomic DNA from tissue. Thirty patients (46%) had EBV+ tumors. Expression of HLA class I (p = 0.0006) was significantly associated with EBV+ tumor status in Hispanic patients, similar to Europeans and Chinese. A positive association between HLA class II expression and EBV+ tumor status, as present in large studies in Europeans, was not found (p = 0.06). The prevalences of the specific European HLA-A*01 risk and European HLA-A*02 protective types were not significantly associated with EBV+ tumors among these Hispanic patients, however numbers were too low to draw firm conclusions. The HLA-A*02:07 allele, that is associated with EBV+ Hodgkin lymphoma in Chinese, was absent. In conclusion, the association between EBV positivity in tumor cells and HLA class I expression appears to be consistent across different populations. Larger studies in Hispanics are needed to evaluate HLA allele susceptibility associations.

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“…The HLA background of cHL patients may also have a role in this respect and, more importantly, in dictating the inherent risk to develop an EBV‐positive cHL. Indeed, several studies have shown that the HLA‐A*02 allele is protective against EBV‐positive cHL, and this association has been recently substantiated by the demonstration that the subdominant T‐cell responses to LMP‐1 and LMP‐2 epitopes is largely confined to patients carrying this allele …”

Section: Microenvironmental Impact Of Ebv Infectionmentioning

confidence: 94%

“…Indeed, several studies have shown that the HLA-A*02 allele is protective against EBVpositive cHL, [69][70][71][72] and this association has been recently substantiated by the demonstration that the subdominant T-cell responses to LMP-1 and LMP-2 epitopes is largely confined to patients carrying this allele. 73 Tumor microenvironment of EBV-positive cHLs is also characterized by a more pronounced infiltration by macrophages as compared with EBV-negative cases. In fact, a prominent signature including the overexpression of macrophage-related genes was identified in EBV-positive cHLs by gene expression profiling of whole tumor tissues.…”

Section: Microenvironmental Impact Of Ebv Infectionmentioning

confidence: 99%

The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis

et al. 2016

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The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so-called Hodgkin and Reed-Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL-derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumor cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease. In 20-40% of cHL cases, HRS cells carry a monoclonal infection by Epstein Barr virus (EBV), which is considered a tumor-initiating factor. In these cases, EBV shows a latency type II infection pattern with the expression of latent membrane protein-1 (LMP-1), a viral oncoprotein that mimics CD40 activation. This scenario is particularly intriguing for the pathogenesis of cHL arising in HIV-infected patients, which, for still obscure reasons, is invariably EBV-associated with LMP-1 expression in HRS cells. Recent evidences are consistent with the occurrence of different pathogenic pathways variably triggered by virus infections (EBV and HIV), genetic alterations, and interactions with critical microenvironmental components. This review focuses on the different microenvironmental niches that characterize cHL of the general population as well as cases of HIV-infected patients. A more comprehensive understanding of the complex interplay existing between HRS and tumor microenvironment is pivotal for the development of more effective treatments, particularly for relapsed or refractory diseases.

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

Cited by 39 publications

References 68 publications

Proteome-Wide Analysis of Cd8+ T Cell Responses to Ebv Reveals Differences Between Primary and Persistent Infection

Proteome-Wide Analysis of Cd8+ T Cell Responses to Ebv Reveals Differences Between Primary and Persistent Infection

HLA expression and HLA type associations in relation to EBV status in Hispanic Hodgkin lymphoma patients

The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis

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