scholarly journals The Epstein-Barr Virus Major Tegument Protein BNRF1 Is a Common Target of Cytotoxic CD4+ T Cells

2020 ◽  
Vol 94 (15) ◽  
Author(s):  
Dinesh Adhikary ◽  
Julia Damaschke ◽  
Josef Mautner ◽  
Uta Behrends
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Response Rates ◽  
T Cell Response ◽  
Tegument Protein ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Health And Disease ◽  
Epstein Barr

ABSTRACT Cellular immunotherapy is a proven approach against Epstein-Barr virus (EBV)-driven lymphoproliferation in recipients of hematopoietic stem cells. Extending the applicability and improving the response rates of such therapy demands improving the knowledge base. We studied 23 healthy donors for specific CD4+ T cell responses against the viral tegument protein BNRF1 and found such T cells in all seropositive donors, establishing BNRF1 as an important immune target in EBV. We identified 18 novel immune epitopes from BNRF1, all of them generated by natural processing of the full-length protein from virus-transformed lymphoblastoid cell lines (LCL). BNRF1-specific CD4+ T cells were measured directly ex vivo by a cytokine-based method, thus providing a tool to study the interaction between immunity and infection in health and disease. T cells of the cytotoxic Th1 type inhibited the proliferation of autologous LCL as well as virus-driven transformation. We infer that they are important in limiting reactivations to subclinical levels during health and reducing virus propagation during disease. The information obtained from this work will feed into data sets that are indispensable in the design of patient-tailored immunotherapeutic approaches, thereby enabling the stride toward broader application of T cell therapy and improving clinical response rates. IMPORTANCE Epstein-Barr virus is carried by most humans and can cause life-threatening diseases. Virus-specific T cells have been used in different clinical settings with variable success rates. One way to improve immunotherapy is to better suit T cell generation protocols to viral targets available in different diseases. BNRF1 is present in viral particles and therefore likely available as a target for T cells in diseases with virus amplification. Here, we studied healthy Epstein-Barr virus (EBV) carriers for BNRF1 immunogenicity and report our results indicating BNRF1 to be a dominant target of the EBV-specific CD4+ T cell response. BNRF1-specific CD4+ T cells were found to be cytotoxic and capable of limiting EBV-driven B cell transformation in vitro. The findings of this work contribute to forwarding our understanding of host-virus interactions during health and disease and are expected to find direct application in the generation of specific T cells for immunotherapy.

scholarly journals Direct Visualization of Antigen-specific CD8+T Cells during the Primary Immune Response to Epstein-Barr Virus In Vivo

1998 ◽  
Vol 187 (9) ◽  
pp. 1395-1402 ◽  
Author(s):  
M.F.C. Callan ◽  
L. Tan ◽  
N. Annels ◽  
G.S. Ogg ◽  
J.D.K. Wilson ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Epstein Barr Virus ◽  
T Cell Response ◽  
Primary Immune Response ◽  
Barr Virus ◽  
Epstein Barr

Primary infection with virus can stimulate a vigorous cytotoxic T cell response. The magnitude of the antigen-specific component versus the bystander component of a primary T cell response remains controversial. In this study, we have used tetrameric major histocompatibility complex–peptide complexes to directly visualize antigen-specific cluster of differentration (CD)8+ T cells during the primary immune response to Epstein-Barr virus (EBV) infection in humans. We show that massive expansion of activated, antigen-specific T cells occurs during the primary response to this virus. In one individual, T cells specific for a single EBV epitope comprised 44% of the total CD8+ T cells within peripheral blood. The majority of the antigen-specific cells had an activated/memory phenotype, with expression of human histocompatibility leukocyte antigen (HLA) DR, CD38, and CD45RO, downregulation of CD62 leukocyte (CD62L), and low levels of expression of CD45RA. After recovery from AIM, the frequency of antigen-specific T cells fell in most donors studied, although populations of antigen-specific cells continued to be easily detectable for at least 3 yr.

scholarly journals 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

2000 ◽  
Vol 74 (14) ◽  
pp. 6675-6679 ◽  
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.

scholarly journals T Cell Epitope Clustering in the Highly Immunogenic BZLF1 Antigen of Epstein-Barr Virus

2014 ◽  
Vol 89 (1) ◽  
pp. 703-712 ◽  
Author(s):  
Melissa J. Rist ◽  
Michelle A. Neller ◽  
Jacqueline M. Burrows ◽  
Scott R. Burrows
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Epstein Barr Virus ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Barr Virus ◽  
Epstein Barr ◽  
Hla Molecules

ABSTRACTPolymorphism in the human leukocyte antigen (HLA) loci ensures that the CD8+T cell response to viruses is directed against a diverse range of antigenic epitopes, thereby minimizing the impact of virus escape mutation across the population. The BZLF1 antigen of Epstein-Barr virus is an immunodominant target for CD8+T cells, but the response has been characterized only in the context of a limited number of HLA molecules due to incomplete epitope mapping. We have now greatly expanded the number of defined CD8+T cell epitopes from BZLF1, allowing the response to be evaluated in a much larger proportion of the population. Some regions of the antigen fail to be recognized by CD8+T cells, while others include clusters of overlapping epitopes presented by different HLA molecules. These highly immunogenic regions of BZLF1 include polymorphic sequences, such that up to four overlapping epitopes are impacted by a single amino acid variation common in different regions of the world. This focusing of the immune response to limited regions of the viral protein could be due to sequence similarity to human proteins creating “immune blind spots” through self-tolerance. This study significantly enhances the understanding of the immune response to BZLF1, and the precisely mapped T cell epitopes may be directly exploited in vaccine development and adoptive immunotherapy.IMPORTANCEEpstein-Barr virus (EBV) is an important human pathogen, associated with several malignancies, including nasopharyngeal carcinoma and Hodgkin lymphoma. T lymphocytes are critical for virus control, and clinical trials aimed at manipulating this arm of the immune system have demonstrated efficacy in treating these EBV-associated diseases. These trials have utilized information on the precise location of viral epitopes for T cell recognition, for either measuring or enhancing responses. In this study, we have characterized the T cell response to the highly immunogenic BZLF1 antigen of EBV by greatly expanding the number of defined T cell epitopes. An unusual clustering of epitopes was identified, highlighting a small region of BZLF1 that is targeted by the immune response of a high proportion of the world's population. This focusing of the immune response could be utilized in developing vaccines/therapies with wide coverage, or it could potentially be exploited by the virus to escape the immune response.

scholarly journals Primary Epstein-Barr virus infection does not erode preexisting CD8+ T cell memory in humans

2012 ◽  
Vol 209 (3) ◽  
pp. 471-478 ◽  
Author(s):  
Oludare A. Odumade ◽  
Jennifer A. Knight ◽  
David O. Schmeling ◽  
David Masopust ◽  
Henry H. Balfour ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

Acute Epstein-Barr virus (EBV) infection results in an unusually robust CD8+ T cell response in young adults. Based on mouse studies, such a response would be predicted to result in attrition of preexisting memory to heterologous infections like influenza A (Flu) and cytomegalovirus (CMV). Furthermore, many studies have attempted to define the lymphocytosis that occurs during acute EBV infection in humans, but it is unclear whether bystander T cells contribute to it. To address these issues, we performed a longitudinal prospective study of primary EBV infection in humans. During acute EBV infection, both preexisting CMV- and Flu-specific memory CD8+ T cells showed signs of bystander activation, including up-regulation of granzyme B. However, they generally did not expand, suggesting that the profound CD8+ lymphocytosis associated with acute EBV infection is composed largely of EBV-specific T cells. Importantly, the numbers of CMV- and Flu-specific T cells were comparable before and after acute EBV infection. The data support the concept that, in humans, a robust CD8+ T cell response creates a new memory CD8+ T cell niche without substantially depleting preexisting memory for heterologous infections.

scholarly journals Efficient Class II Major Histocompatibility Complex Presentation of Endogenously Synthesized Hepatitis C Virus Core Protein by Epstein-Barr Virus-Transformed B-Lymphoblastoid Cell Lines to CD4+ T Cells

1998 ◽  
Vol 72 (10) ◽  
pp. 8301-8308 ◽  
Author(s):  
Ming Chen ◽  
Mutsunori Shirai ◽  
Zijuan Liu ◽  
Tatsumi Arichi ◽  
Hidemi Takahashi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Core Protein ◽  
Class Ii ◽  
T Cell Response ◽  
Barr Virus ◽  
Histocompatibility Complex ◽  
Epstein Barr

ABSTRACT The induction of an efficient CD4+ T-cell response against hepatitis C virus (HCV) is critical for control of the chronicity of HCV infection. The ability of HCV structural protein endogenously expressed in an antigen-presenting cell (APC) to be presented by class II major histocompatibility complex molecules to CD4+ T cells was investigated by in vitro culture analyses using HCV core-specific T-cell lines and autologous Epstein-Barr virus-transformed B-lymphoblastoid cell lines (B-LCLs) expressing structural HCV antigens. The T- and B-cell lines were generated from peripheral blood mononuclear cells derived from HCV-infected patients. Expression and intracellular localization of core protein in transfected cells were determined by immunoblotting and immunofluorescence. By stimulation with autologous B-LCLs expressing viral antigens, strong T-cell proliferative responses were induced in two of three patients, while no substantial stimulatory effects were produced by B-LCLs expressing a control protein (chloramphenicol acetyltransferase) or by B-LCLs alone. The results showed that transfected B cells presented mainly endogenously synthesized core peptides. Presentation of secreted antigens from adjacent antigen-expressing cells was not enough to stimulate a core-specific T-cell response. Only weak T-cell proliferative responses were generated by stimulation with B-LCLs that had been pulsed beforehand with at least a 10-fold-higher amount of transfected COS cells in the form of cell lysate, suggesting that presentation of antigens released from dead cells in the B-LCL cultures had a minimal role. Titrating numbers of APCs, we showed that as few as 104 transfected B-LCL APCs were sufficient to stimulate T cells. This presentation pathway was found to be leupeptin sensitive, and it can be blocked by antibody to HLA class II (DR). In addition, expression of a costimulatory signal by B7/BB1 on B cells was essential for T-cell activation.

Skewed TCR Repertoire of Vδ1+ γδT Cells in Recipients of Allogeneic Hematopoietic Stem Cell Grafts and Possible Involvement of Epstein-Barr Virus in Clonal Expansion of Vδ1+ T Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2230-2230
Author(s):  
Masumi Fujishima ◽  
Makoto Hirokawa ◽  
Naohito Fujishima ◽  
Hirobumi Saitoh ◽  
Yoshikazu Ichikawa ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Clinical Outcome ◽  
Epstein Barr Virus ◽  
Clonal Expansion ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Cdr3 Region ◽  
Epstein Barr

Abstract Background: We previously demonstrated that stable clonal expansion of Vδ1+ γδT lymphocytes persisted for several years after human allogeneic hematopoietic stem cell transplantation (allo-HSCT). These Vδ1+ T cells are derived from mature T cells in the graft. In the present study, we have extended our observation to learn whether oligoclonal expansions of Vδ1+ γδT lymphocytes might be associated with clinical outcome and GVHD, and whether consensus sequences of the CDR3 region of clonally expanded Vδ1+ T cells would be observed among different individuals. We also examined the possible role for Epstein-Barr virus (EBV) in clonal expansion of Vδ1+ T cells. Methods: Forty-two patients receiving allo-HSCT for hematological malignancies were included in this study. Grafts included bone marrow (n=33), G-CSF mobilized peripheral blood stem cells (n=7) and cord blood (n=2). Clonality of the Vδ1+ T cell subset was determined by CDR3 size spectratyping analysis. Junctional sequences were determined by DNA sequencing. In some experiments, PBMCs from healthy volunteer donors were stimulated with autologous EBV-LCL and were analyzed for clonality of TCRs. Results: CDR3 size spectratyping analysis revealed that twenty-three out of forty-two patients had highly skewed TCR repertoires of the Vδ1+ T cells. There was no apparent association between the oligoclonality of Vδ1+ TCRs and clinical outcome such as GVHD and leukemia relapse. In eight out of seventeen patients examined, the -WGI- amino acid sequence was observed in the CDR3 region of TCRs of clonally expanded Vδ1+ T cells. The -YWG- sequence was observed in four patients. All recipients examined were serologically positive for EBV-VCA IgG and EBNA. Bacterial or fungal components failed to stimulate Vδ1+ T cells to proliferate in vitro, but autologous EBV transformed B cells could induce the expansion of Vδ1+ T cells. The CDR3 size distribution patterns of Vδ1+ TCRs became skewed after stimulation with autologous EBV-LCL, and the T cell clone with the -LEEYWGLPH- CDR3 sequence predominated in the culture with autologous EBV-LCL, whereas this clone was not detectable before culture. Moreover, allogeneic EBV-positive Raji cells also induced the oligoclonal expansion of Vδ1+ T cells carrying the -WGI- or -YWG- junctional sequence. These results suggest the CDR3 structure may contribute to recognition of EBV-associated antigens by Vδ1+ T cells Conclusion: Skewing of the Vδ1+ TCR after allo-HSCT may be the result of the response to infectious antigens widely existing in humans such as EBV. Table 1. Junctional diversity of Vδ1 TCR of γδ T cells expanded in response to autologous EBV-LCL and allogeneic Burkitt lymphoma cells Stimulation δV1 N-D-N Jδ Colony frequency T cell clones appearing more than once are presented. Nil CALGE GLPHALIMWGDLAY TDKLIFGKG 3/20 EBV-LCL CALGE LEEYWGLPH TDKLIFGKG 10/27 CALGE GLPHALIMWGDLAY TDKLIFGKG 7/27 CALG GVLYWGIRR TDKLIFGKG 2/27 CALGE SLWGIRY TDKLIFGKG 2/27 CALGE LGETTPLLGGYSFA LTAQLFFGKG 2/27 Raji CALG VSGLARGGSL KLIFGKG 6/25 CALGE ADWGIRARILY TDKLIFGKG 4/25 CALGE PRAILGDTRIKRMY TDKLIFGKG 4/25 CALGE LEEYWGLPH TDKLIFGKG 3/25 CALGE DPGLPFLWY TDKLIFGKG 2/25 CALG DLNLLWGIRSILPG TDKLIFGKG 2/25

scholarly journals How I treat T-cell chronic active Epstein-Barr virus disease

Blood ◽  
2018 ◽  
Vol 131 (26) ◽  
pp. 2899-2905 ◽  
Author(s):  
Catherine M. Bollard ◽  
Jeffrey I. Cohen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Histone Deacetylase Inhibitors ◽  
Virus Disease ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Barr Virus ◽  
Epstein Barr

Abstract T-cell chronic active Epstein-Barr virus (CAEBV) is a rare disease in which EBV is present predominantly in T cells that infiltrate the tissues; patients have high levels of EBV in the blood. If untreated, patients often develop liver failure, hemophagocytic lymphohistiocytosis, coronary artery aneurysms, EBV infiltrating T cells impairing organ function, or T-cell lymphomas refractory to treatment. At present, hematopoietic stem-cell transplantation is the only curative therapy, and it is critical to make a proper diagnosis and initiate transplantation before the disease progresses to an irreversible stage. Specific medications such as high-dose systemic corticosteroids or ganciclovir combined with either histone deacetylase inhibitors or bortezomib may temporarily reduce systemic toxicity associated with T-cell CAEBV and allow the patient time to receive a transplant. Relapses of the disease after transplantation have also occurred, and the use of donor-derived virus-specific T cells may help to treat these relapses.

scholarly journals Effect of methotrexate and anti-TNF on Epstein-Barr virus T-cell response and viral load in patients with rheumatoid arthritis or spondylarthropathies

2009 ◽  
Vol 11 (3) ◽  
pp. R77 ◽  
Author(s):  
Corinne Miceli-Richard ◽  
Nicolas Gestermann ◽  
Corinne Amiel ◽  
Jérémie Sellam ◽  
Marc Ittah ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Viral Load ◽  
T Cell ◽  
Cell Response ◽  
Epstein Barr Virus ◽  
T Cell Response ◽  
Barr Virus ◽  
Epstein Barr

Peripheral T-cell Lymphoma, NOS With Epstein-Barr Virus Positivity in an Elderly Patient With Myelodysplastic Syndrome: An Autopsy Case Report

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S81-S81
Author(s):  
J Lanceta ◽  
W Xue ◽  
M Hurford ◽  
H Wu
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Barr Virus ◽  
Epstein Barr

Abstract Casestudy Epstein-Barr virus (EBV)-associated peripheral T-cell lymphomas are a group of aggressive neoplasms with a geographic predilection for South America and Asia, but are very rare in Western populations. Results We report a case of a 74-year-old Caucasian female who presented with pancytopenia and B symptoms with EBV-IgG detected on admission. Past medical history included: ITP, chronic urticaria, and recently diagnosed myelodysplastic syndrome (MDS) on bone marrow biopsy one month prior to admission. Excisional biopsies of an enlarged right neck lymph node (repeated within 6 months) and right axillary lymph node five years ago were negative for a lymphoproliferative disorder at the time. Repeated bone marrow biopsy, performed during the current admission, confirmed the diagnosis of MDS, with scattered T-cells without aberrant immunophenotype. Despite aggressive treatment from multiple specialties, the patient deteriorated and expired four weeks later from complications of MDS. At autopsy, there was diffuse lymphadenopathy involving the mediastinum, axilla, pelvis and peripancreatic fat. Lymph node sections demonstrated nodal architecture effacement by diffuse, vaguely nodular lymphoid infiltrates. Histologically, the infiltrates were composed of medium to large lymphocytes with round to slight irregular nuclei, rare Reed-Sternberg-like multinucleated cells, clumped chromatin, and indistinct nucleoli. Individual cell necrosis was abundant with mitotic figures readily identifiable. Immunohistochemistry revealed CD2+ CD3+ neoplastic T-cells that co-express MUM1 and a subset of CD30, while negative for CD4, CD5, CD8, CD56, ALK1, and TDT. EBV-encoded RNA in-situ hybridization was focally positive. The final postmortem diagnosis was peripheral T-cell lymphoma, not otherwise specified (NOS), with focal EBV positivity. Conclusion Co-existence of a de-novo MDS and non-Hodgkin lymphoma without any prior chemotherapeutic exposure is a highly unusual finding, although MDS-like presentations can occur with EBV-associated lymphomas. Peripheral T-cell lymphoma, NOS is an aggressive lymphoma and EBV positivity has been found correlated with a poor prognosis. This case demonstrates how postmortem examination remains an important tool in clinical- pathological correlation and highlights the potential pathogenetic role EBV plays in MDS and T-cell lymphoma.

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