EBNA1-specific CD4+ T cells in healthy carriers of Epstein-Barr virus are primarily Th1 in function

Bickham, Kara; Münz, Christian; Tsang, Ming Li; Larsson, Marie; Fonteneau, Jean-François; Bhardwaj, Nina; Steinman, Ralph M.

doi:10.1172/jci10209

Cited by 114 publications

(94 citation statements)

References 56 publications

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“…EBNA-1-specific CD4ϩ T cells (45,46), mainly of the Th1 phenotype (47), have recently been detected in healthy EBV carriers and may provide help for the production of antibodies directed to the different epitopes of this protein. In the presence of a higher EBV load, events such as apoptosis, infection, damage, or any stimulus involving calcium influx may activate PAD, which is highly expressed in RA synovia (48,49), and induce the deimination of different proteins, including viral proteins.…”

Section: Discussionmentioning

confidence: 99%

Deiminated Epstein‐Barr virus nuclear antigen 1 is a target of anti–citrullinated protein antibodies in rheumatoid arthritis

Pratesi

Tommasi

Anzilotti

et al. 2006

Arthritis & Rheumatism

120

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Objective. To test the hypothesis that deimination of viral sequences containing Arg-Gly repeats could generate epitopes recognized by anti-citrullinated protein antibodies (ACPAs) that are present in rheumatoid arthritis (RA) sera.Methods. Multiple antigen peptides derived from Epstein-Barr virus (EBV)-encoded Epstein-Barr nuclear antigen 1 (EBNA-1) were synthesized, substituting the arginines with citrulline, and were used to screen RA sera. Anti-cyclic citrullinated peptide antibodies were purified by affinity chromatography and tested on a panel of in vitro deiminated proteins. Their ability to bind in vivo deiminated proteins was evaluated by immunoprecipitation, using EBV-infected cell lines.Results. Antibodies specific for a peptide corresponding to the EBNA-1 35-58 sequence containing citrulline in place of arginine (viral citrullinated peptide [VCP]) were detected in 50% of RA sera and in <5% of normal and disease control sera. In addition, affinitypurified anti-VCP antibodies from RA sera reacted with filaggrin-derived citrullinated peptides, with deiminated fibrinogen, and with deiminated recombinant EBNA-1. Moreover, anti-VCP antibodies immunoprecipitated, from the lysate of calcium ionophore-stimulated lymphoblastoid cell lines, an 80-kd band that was reactive with a monoclonal anti-EBNA-1 antibody and with anti-modified citrulline antibodies.Conclusion. These data indicate that ACPAs react with a viral deiminated protein and suggest that EBV infection may play a role in the induction of these RA-specific antibodies.

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Section: Discussionmentioning

confidence: 99%

Deiminated Epstein‐Barr virus nuclear antigen 1 is a target of anti–citrullinated protein antibodies in rheumatoid arthritis

Pratesi

Tommasi

Anzilotti

et al. 2006

Arthritis & Rheumatism

120

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“…46 For EBV, it is clear that DCs present several latency antigens (EBNA1, LMP1, LMP2 and EBNA3) to CD4 and/or CD8 T cells, using many different sources of antigen, i.e., peptides, proteins encoded by recombinant viral vectors and dead EBV-transformed B cells. 157,189,231,232 Viruses associated with human malignancy pose 2 other challenges for immunotherapy. First, mucosal immunization may be valuable.…”

Section: Virus-associated Malignanciesmentioning

confidence: 99%

“…Healthy adults reliably recognize the EBNA1 antigen, 157 essential for maintenance of EBV in growing cells. The CD4 ϩ EBNA1 response is of the protective Th1 type, 232 one of the only examples of a naturally polarized Th1 response in humans. These observations suggest that CD4 ϩ T-cell immunity of the Th1 type is a valuable component of a protective response to a cancercausing virus.…”

Section: Virus-associated Malignanciesmentioning

confidence: 99%

Active immunization against cancer with dendritic cells: The near future

2001

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DCs 1 are antigen-presenting cells that regulate several components of the immune system. The mature or terminal stage of DC development induces specific T-cell immunity and resistance to experimental tumors in vivo. However, DC maturation is induced by inflammatory and microbial stimuli, so it is unlikely that mature DCs normally present antigens from tumor cells in cancer patients. Accordingly, clinical studies have begun in which DCs are generated ex vivo, charged with tumor antigens, exposed to maturation stimuli and reinfused to immunize patients. This approach has the potential to control responses to cancer antigens in a specific and nontoxic manner, in both vaccination and therapeutic settings.DCs can mobilize several immune resistance mechanisms. These include CD8ϩ CTLs, CD4 ϩ helper T cells, NK and NKT cells. Each of these lymphocytes recognizes targets through a distinct mechanism and has the capacity to kill tumor cells and release valuable protective cytokines like IFN-␥. CD4 ϩ T cells also provide essential help for the expansion and maintenance of CD8 ϩ cytolytic cells, while NK and NKT cells can eliminate targets that dampen presentation on MHC class I to escape CTL recognition. The stimulation and concerted action of these classes of lymphocytes can now be studied directly in patients, using ex vivo-derived DCs.Several findings have emerged from studies of healthy volunteers who have been immunized with DCs charged with model antigens, KLH protein and influenza virus matrix peptide. Mature DCs elicit a polarized Th1 type of CD4 T-cell response, only a single injection being required. Vaccination with antigen-bearing DCs also markedly improves the functional affinity of CD8 ϩ T cells. These findings are important in the context of immunotherapy because Th1 cells are more efficient helper cells in experimental models of viral infection and tumors, while high-affinity CTLs should improve recognition of tumor-derived peptides. An important caution also has surfaced when DCs are not adequately differentiated. Immature DCs can silence adaptive T-cell responses, e.g., by inducing IL-10 -producing, T-reg cells.DC-based active immunization does not result in major shortterm toxicity in healthy subjects or cancer patients. Tumor-specific T-cell responses have been induced and detected in fresh blood specimens without the need for restimulation in vitro. However, the immune responses observed in the first protocols are still smaller than those seen naturally in acute viral infections. Occasional clinical regressions have been noted in these initial feasibility studies, particularly in melanomas, pediatric tumors, lymphomas, prostate cancers and renal cell cancers. This information, coupled with progress in DC biology, suggests many ways to improve the efficacy of this new therapy. Some relevant topics include antigen loading and DC maturation procedures, frequency and route of DC injection, efficiency of DC homing to lymphoid tissues and their longevity once there and the role of distinct DC subsets. A val...

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“…Thus, even in the absence of all other EBV proteins, such as in Burkitt lymphoma, EBNA1 expression must be maintained, and from an immune surveillance point of view, EBNA1 should be a critical target of protective immunity. Indeed, EBNA1 is consistently recognized by Th1-type CD4 ϩ T cells, [3][4][5][6] and can elicit CD8 ϩ T-cell responses 7-9 in healthy EBV carriers. These T cells that recognize mostly epitopes in the C-terminal domain of EBNA1 can target EBV-transformed B cells and prevent their outgrowth in vitro.…”

Section: Introductionmentioning

confidence: 99%

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

Gurer

Strowig

Brilot

et al. 2008

Blood

Self Cite

121

129

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IntroductionEpstein-Barr virus (EBV) is a ubiquitous human ␥-herpesvirus that latently infects B cells and establishes chronic infection in more than 90% of the adult population. Although infection with EBV during adolescence can lead to infectious mononucleosis (IM), the vast majority of infected people acquires and harbors EBV as a benign lifelong infection, which is controlled by strong T-cell immunity. However, in a small subset of infected individuals, EBV latency programs with different viral antigen expression patterns are associated with malignancies such as Hodgkin and Burkitt lymphomas as well as nasopharyngeal carcinoma (NPC). 1 The nuclear antigen 1 (EBNA1) is the one EBV antigen that is expressed in all of these EBV-associated tumors as well as in EBV-positive proliferating cells in healthy carriers. 2 EBNA1 is crucial for viral persistence, because it initiates viral DNA replication and anchors the circular viral episome to the mitotic chromosomes during cell division, thereby ensuring the survival of the viral genome in proliferating cells. Thus, even in the absence of all other EBV proteins, such as in Burkitt lymphoma, EBNA1 expression must be maintained, and from an immune surveillance point of view, EBNA1 should be a critical target of protective immunity. Indeed, EBNA1 is consistently recognized by Th1-type CD4 ϩ T cells, [3][4][5][6] and can elicit CD8 ϩ T-cell responses 7-9 in healthy EBV carriers. These T cells that recognize mostly epitopes in the C-terminal domain of EBNA1 can target EBV-transformed B cells and prevent their outgrowth in vitro. 10 While EBNA1-specific T-cell responses can also be detected in peripheral blood of NPC patients, 11 they are greatly diminished in patients with EBVassociated non-Hodgkin lymphoma in the context of HIV infection, 12 EBV-associated Hodgkin disease (K. N. Heller, F.A., P. Steinherz, C. Postlook, A. Chadburn, K. Kelly, C.M., manuscript submitted) and endemic Burkitt lymphomas (Ann Moormann, Case Western Reserve University, Cleveland, OH, personal communication April 2008), thus making EBNA1, and specifically its C-terminal domain, a logical target for vaccine development against all EBV-associated malignancies.A promising cell type, to which EBNA1 could be targeted for vaccine design, is dendritic cells (DCs). These sentinels of the immune system have an exceptional T-cell stimulatory capacity, which includes their ability to efficiently process antigens, and present them on both major histocompatibility class (MHC) I and class II molecules in combination with T-cell costimulatory molecules. 13 DCs are also crucial for initiating protective innate and adaptive immune responses against bacterial and viral pathogens in vivo, 14,15 which further supports targeting DCs for therapeutic vaccination. However, many current DC-targeted immunization approaches use individualized culture, antigen loading, and activation of DCs in vitro for adoptive transfer. 16 A more recent strategy that circumvents the analysis of ex vivo DCs is to target antigens to DCs in...

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EBNA1-specific CD4+ T cells in healthy carriers of Epstein-Barr virus are primarily Th1 in function

Cited by 114 publications

References 56 publications

Deiminated Epstein‐Barr virus nuclear antigen 1 is a target of anti–citrullinated protein antibodies in rheumatoid arthritis

Deiminated Epstein‐Barr virus nuclear antigen 1 is a target of anti–citrullinated protein antibodies in rheumatoid arthritis

Active immunization against cancer with dendritic cells: The near future

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

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