Epstein-Barr virus (EBV) antigens processed and presented by B cells, B blasts, and macrophages trigger T-cell-mediated inhibition of EBV-induced B-cell transformation.

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a peculiar T cell lymphoma, as expanding B cell clones are often present besides the malignant T cell clones. In addition, large numbers of Epstein-Barr virus (EBV)-infected B cells are frequently observed. To analyze the differentiation status and clonal composition of EBV-harboring B cells in AILD, single EBV-infected cells were micromanipulated from lymph nodes of six patients with frequent EBV+ cells and their rearranged immunoglobulin (Ig) genes analyzed. Most EBV-infected B cells carried mutated Ig genes, indicating that in AILD, EBV preferentially resides in memory and/or germinal center B cells. EBV+ B cell clones observed in all six cases ranged from small polyclonal to large monoclonal expansions and often showed ongoing somatic hypermutation while EBV− B cells showed little tendency for clonal expansion. Surprisingly, many members of expanding B cell clones had acquired destructive mutations in originally functional V gene rearrangements and showed an unfavorable high load of replacement mutations in the framework regions, indicating that they accumulated mutations over repeated rounds of mutation and division while not being selected through their antigen receptor. This sustained selection-free accumulation of somatic mutations is unique to AILD. Moreover, the survival and clonal expansion of “forbidden” (i.e., Ig-deficient) B cells has not been observed before in vivo and thus represents a novel type of viral latency in the B cell compartment. It is likely the interplay between the microenvironment in AILD lymph nodes and the viral transformation that leads to the survival and clonal expansion of Ig-less B cells.

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Knockout of Epstein-Barr Virus BPLF1 Retards B-Cell Transformation and Lymphoma Formation in Humanized Mice

mBio ◽

10.1128/mbio.01574-15 ◽

2015 ◽

Vol 6 (5) ◽

Cited By ~ 29

Author(s):

Christopher B. Whitehurst ◽

Guangming Li ◽

Stephanie A. Montgomery ◽

Nathan D. Montgomery ◽

Lishan Su ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Epstein Barr Virus ◽

Cell Transformation ◽

Lytic Cycle ◽

Humanized Mice ◽

Barr Virus ◽

Epstein Barr ◽

Knockout Virus ◽

Large B Cell

ABSTRACTBPLF1 of Epstein-Barr virus (EBV) is classified as a late lytic cycle protein but is also found in the viral tegument, suggesting its potential involvement at both initial and late stages of viral infection. BPLF1 possesses both deubiquitinating and deneddylating activity located in its N-terminal domain and is involved in processes that affect viral infectivity, viral DNA replication, DNA repair, and immune evasion. A recently constructed EBV BPLF1-knockout (KO) virus was used in conjunction with a humanized mouse model that can be infected with EBV, enabling the first characterization of BPLF1 functionin vivo. Results demonstrate that the BPLF1-knockout virus is approximately 90% less infectious than wild-type (WT) virus. Transformation of human B cells, a hallmark of EBV infection, was delayed and reduced with BPLF1-knockout virus. Humanized mice infected with EBV BPLF1-knockout virus showed less weight loss and survived longer than mice infected with equivalent infectious units of WT virus. Additionally, splenic tumors formed in 100% of mice infected with WT EBV but in only 25% of mice infected with BPLF1-KO virus. Morphological features of spleens containing tumors were similar to those in EBV-induced posttransplant lymphoproliferative disease (PTLD) and were almost identical to cases seen in human diffuse large B-cell lymphoma. The presence of EBV genomes was detected in all mice that developed tumors. The results implicate BPLF1 in human B-cell transformation and tumor formation in humanized mice.IMPORTANCEEpstein-Barr virus infects approximately 90% of the world's population and is the causative agent of infectious mononucleosis. EBV also causes aggressive lymphomas in individuals with acquired and innate immune disorders and is strongly associated with diffuse large B-cell lymphomas, classical Hodgkin lymphoma, Burkitt lymphoma, and nasopharyngeal carcinoma (NPC). Typically, EBV initially infects epithelial cells in the oropharynx, followed by a lifelong persistent latent infection in B-cells, which may develop into lymphomas in immunocompromised individuals. This work is the first of its kind in evaluating the effects of EBV's BPLF1 in terms of pathogenesis and lymphomagenesis in humanized mice and implicates BPLF1 in B-cell transformation and tumor development. Currently, there is no efficacious treatment for EBV, and therapeutic targeting of BPLF1 may lead to a new path to treatment for immunocompromised individuals or transplant recipients infected with EBV.

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Functional interplay of Epstein-Barr virus oncoproteins in a mouse model of B cell lymphomagenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1921139117 ◽

2020 ◽

Vol 117 (25) ◽

pp. 14421-14432

Author(s):

Thomas Sommermann ◽

Tomoharu Yasuda ◽

Jonathan Ronen ◽

Tristan Wirtz ◽

Timm Weber ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Epstein Barr Virus ◽

Plasma Cells ◽

Cell Transformation ◽

Barr Virus ◽

Nuclear Antigens ◽

Epstein Barr ◽

Cell Transforming ◽

Early B Cell Factor

Epstein-Barr virus (EBV) is a B cell transforming virus that causes B cell malignancies under conditions of immune suppression. EBV orchestrates B cell transformation through its latent membrane proteins (LMPs) and Epstein-Barr nuclear antigens (EBNAs). We here identify secondary mutations in mouse B cell lymphomas induced by LMP1, to predict and identify key functions of other EBV genes during transformation. We find aberrant activation of early B cell factor 1 (EBF1) to promote transformation of LMP1-expressing B cells by inhibiting their differentiation to plasma cells. EBV EBNA3A phenocopies EBF1 activities in LMP1-expressing B cells, promoting transformation while inhibiting differentiation. In cells expressing LMP1 together with LMP2A, EBNA3A only promotes lymphomagenesis when the EBNA2 target Myc is also overexpressed. Collectively, our data support a model where proproliferative activities of LMP1, LMP2A, and EBNA2 in combination with EBNA3A-mediated inhibition of terminal plasma cell differentiation critically control EBV-mediated B cell lymphomagenesis.

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Preferential Localization of the Epstein-Barr Virus (EBV) Oncoprotein LMP-1 to Nuclei in Human T Cells: Implications for Its Role in the Development of EBV Genome-Positive T-Cell Lymphomas

Journal of Virology ◽

10.1128/jvi.76.8.4080-4086.2002 ◽

2002 ◽

Vol 76 (8) ◽

pp. 4080-4086 ◽

Cited By ~ 10

Author(s):

Jingwu Xu ◽

Ali Ahmad ◽

José Menezes

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Epstein Barr Virus ◽

Phenotypic Changes ◽

Barr Virus ◽

T Cell Lymphomas ◽

Cell Clones ◽

Epstein Barr

ABSTRACT The Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP-1) is thought to play a role in the EBV-induced B-cell transformation and immortalization. EBV has also been implicated in certain human T-cell lymphomas; however, the phenotypic effects of the expression of this oncoprotein in T cells are not known. To learn whether LMP-1 also induces phenotypic changes in T cells, we stably expressed it in human cell lines of T and B lineages and 25 LMP-1-expressing T-cell clones and 7 B-cell clones were examined. Our results show for the first time that, in sharp contrast to B cells, LMP-1 preferentially localizes to nuclei in T cells and does not induce the phenotypic changes in these cells that it induces in B cells, does not associate with TRAF proteins, and does not arrest the cell cycle in the G2/M phase. A computer-assisted analysis revealed that LMP-1 lacks the canonical nuclear localization signal. Our results suggest that this oncoprotein may not play the same role in the lymphomagenesis of T cells as it does in B cells.

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T-cell-mediated regression of “spontaneous” and of Epstein-Barr virus-induced B-cell transformation in vitro: Studies with cyclosporin A

Cellular Immunology ◽

10.1016/0008-8749(84)90032-7 ◽

1984 ◽

Vol 87 (2) ◽

pp. 646-658 ◽

Cited By ~ 83

Author(s):

A.B. Rickinson ◽

M. Rowe ◽

I.J. Hart ◽

Q.Y. Yao ◽

L.E. Henderson ◽

...

Keyword(s):

T Cell ◽

Cyclosporin A ◽

B Cell ◽

Epstein Barr Virus ◽

Cell Transformation ◽

In Vitro Studies ◽

Barr Virus ◽

Epstein Barr

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A Rare Case of Angioimmunoblastic T-Cell Lymphoma with Epstein-Barr Virus-Negative Reed-Sternberg-Like B-Cells, Chylous Ascites, and Chylothorax

Case Reports in Hematology ◽

10.1155/2017/1279525 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6

Author(s):

Mathijs Willemsen ◽

Arne W. J. H. Dielis ◽

Iryna V. Samarska ◽

Ad Koster ◽

Arienne M. van Marion

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Rare Case ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

Chylous Ascites ◽

Angioimmunoblastic T Cell Lymphoma ◽

Barr Virus ◽

Epstein Barr

Angioimmunoblastic T-cell lymphoma is a rare non-Hodgkin lymphoma with dismal prognosis. The median age of presentation ranges from 62 to 69 years with generalized lymphadenopathy, B symptoms, and hepatosplenomegaly as the most prevalent symptoms. The combination of B-cell and T-cell proliferations is common in AITL and the B-cell component may resemble Reed-Sternberg-like B-cells. Epstein-Barr virus is estimated to be present in 80–95% of AITL biopsies. Only a handful of EBV-negative AITL cases with EBV-negative RS-like B-cells have been reported over the last decade. We present a rare case of EBV-negative AITL with chylous ascites and chylothorax. Microscopic and immunohistochemical analysis revealed the presence of EBV-negative Reed-Sternberg-like B-cells in the tumor.

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CD4+ T-Cell Effectors Inhibit Epstein-Barr Virus-Induced B-Cell Proliferation

Journal of Virology ◽

10.1128/jvi.75.8.3740-3752.2001 ◽

2001 ◽

Vol 75 (8) ◽

pp. 3740-3752 ◽

Cited By ~ 56

Author(s):

Sarah Nikiforow ◽

Kim Bottomly ◽

George Miller

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Lines ◽

Epstein Barr Virus ◽

Barr Virus ◽

Epstein Barr

ABSTRACT In immunodeficient hosts, Epstein-Barr virus (EBV) often induces extensive B-cell lymphoproliferative disease and lymphoma. Without effective in vitro immune surveillance, B cells infected by the virus readily form immortalized cell lines. In the regression assay, memory T cells inhibit the formation of foci of EBV-transformed B cells that follows recent in vitro infection by EBV. No one has yet addressed which T cell regulates the early proliferative phase of B cells newly infected by EBV. Using new quantitative methods, we analyzed T-cell surveillance of EBV-mediated B-cell proliferation. We found that CD4+ T cells play a significant role in limiting proliferation of newly infected, activated CD23+ B cells. In the absence of T cells, EBV-infected CD23+ B cells divided rapidly during the first 3 weeks after infection. Removal of CD4+ but not CD8+ T cells also abrogated immune control. Purified CD4+ T cells eliminated outgrowth when added to EBV-infected B cells. Thus, unlike the killing of EBV-infected lymphoblastoid cell lines, in which CD8+ cytolytic T cells play an essential role, prevention of early-phase EBV-induced B-cell proliferation requires CD4+ effector T cells.

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Functional Analysis of the CD4+ T-Cell Response to Epstein-Barr Virus: T-Cell-Mediated Activation of Resting B Cells and Induction of Viral BZLF1 Expression

Journal of Virology ◽

10.1128/jvi.74.14.6675-6679.2000 ◽

2000 ◽

Vol 74 (14) ◽

pp. 6675-6679 ◽

Cited By ~ 30

Author(s):

Zheng Fu ◽

Martin J. Cannon

Keyword(s):

Functional Analysis ◽

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Epstein Barr Virus ◽

Lymphoproliferative Disorders ◽

T Cell Response ◽

Barr Virus ◽

Epstein Barr

ABSTRACT In contrast to the major role played by Epstein-Barr virus (EBV)-specific CD8+ cytotoxic T-cell responses in immunosurveillance, recent studies have offered the apparently paradoxical suggestion that development of EBV-driven human B-cell lymphoproliferative disorders and tumors in SCID/hu mice is dependent on the presence of T cells, in particular CD4+ T cells. This study presents a functional analysis of the CD4+T-cell response to EBV and shows that while CD4+ T cells may be cytotoxic, they also express Th2 cytokines and CD40 ligand (gp39) and possess B-cell helper function. We show that EBV-specific CD4+ T cells can provide non-HLA-restricted help for activation of resting B cells via a gp39-CD40-dependent pathway and are able to induce expression of BZLF1, a viral lytic cycle transactivator in latently infected resting B cells, ultimately resulting in rapid outgrowth of transformed B-cell colonies. These results support the proposal that CD4+ T cells may play a key role in reactivation of latent EBV infection and may thus contribute to the pathogenesis of EBV-driven lymphoproliferative disorders.

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Combined immunodeficiency and Epstein-Barr virus–induced B cell malignancy in humans with inherited CD70 deficiency

Journal of Experimental Medicine ◽

10.1084/jem.20160849 ◽

2016 ◽

Vol 214 (1) ◽

pp. 91-106 ◽

Cited By ~ 82

Author(s):

Hassan Abolhassani ◽

Emily S.J. Edwards ◽

Aydan Ikinciogullari ◽

Huie Jing ◽

Stephan Borte ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cd8 T Cells ◽

Epstein Barr Virus ◽

Combined Immunodeficiency ◽

Memory Cd8 T Cells ◽

Barr Virus ◽

Epstein Barr

In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)–related diseases. Three patients presented with EBV-associated Hodgkin’s lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal, but the proportions of memory B cells and EBV-specific effector memory CD8+ T cells were reduced. Furthermore, although T cell proliferation was normal, in vitro–generated EBV-specific cytotoxic T cell activity was reduced because of CD70 deficiency. This reflected impaired activation by, rather than effects during killing of, EBV-transformed B cells. Notably, expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8+ T cells from CD70-deficient individuals was reduced, consistent with their impaired killing of EBV-infected cells. Thus, autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70–CD27 interactions therefore play a nonredundant role in T and B cell–mediated immunity, especially for protection against EBV and humoral immunity.

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The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis

Frontiers in Immunology ◽

10.3389/fimmu.2021.665718 ◽

2021 ◽

Vol 12 ◽

Author(s):

Caterina Veroni ◽

Francesca Aloisi

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cd8 T Cells ◽

Epstein Barr Virus ◽

Cd8 T Cell ◽

Barr Virus ◽

Epstein Barr

The cause and the pathogenic mechanisms leading to multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), are still under scrutiny. During the last decade, awareness has increased that multiple genetic and environmental factors act in concert to modulate MS risk. Likewise, the landscape of cells of the adaptive immune system that are believed to play a role in MS immunopathogenesis has expanded by including not only CD4 T helper cells but also cytotoxic CD8 T cells and B cells. Once the key cellular players are identified, the main challenge is to define precisely how they act and interact to induce neuroinflammation and the neurodegenerative cascade in MS. CD8 T cells have been implicated in MS pathogenesis since the 80’s when it was shown that CD8 T cells predominate in MS brain lesions. Interest in the role of CD8 T cells in MS was revived in 2000 and the years thereafter by studies showing that CNS-recruited CD8 T cells are clonally expanded and have a memory effector phenotype indicating in situ antigen-driven reactivation. The association of certain MHC class I alleles with MS genetic risk implicates CD8 T cells in disease pathogenesis. Moreover, experimental studies have highlighted the detrimental effects of CD8 T cell activation on neural cells. While the antigens responsible for T cell recruitment and activation in the CNS remain elusive, the high efficacy of B-cell depleting drugs in MS and a growing number of studies implicate B cells and Epstein-Barr virus (EBV), a B-lymphotropic herpesvirus that is strongly associated with MS, in the activation of pathogenic T cells. This article reviews the results of human studies that have contributed to elucidate the role of CD8 T cells in MS immunopathogenesis, and discusses them in light of current understanding of autoreactivity, B-cell and EBV involvement in MS, and mechanism of action of different MS treatments. Based on the available evidences, an immunopathological model of MS is proposed that entails a persistent EBV infection of CNS-infiltrating B cells as the target of a dysregulated cytotoxic CD8 T cell response causing CNS tissue damage.

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