scholarly journals Epstein-Barr virus nuclear antigen 1-specific CD4+T cells directly kill Epstein-Barr virus-carrying natural killer and T cells

2008 ◽  
Vol 99 (8) ◽  
pp. 1633-1642 ◽  
Author(s):  
Ayako Demachi-Okamura ◽  
Yoshinori Ito ◽  
Yoshiki Akatsuka ◽  
Kunio Tsujimura ◽  
Yasuo Morishima ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Cd4 T Cells ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr

STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus–encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma

Blood ◽  
2011 ◽  
Vol 117 (1) ◽  
pp. 165-174 ◽  
Author(s):  
Loránd L. Kis ◽  
Natalija Gerasimčik ◽  
Daniel Salamon ◽  
Emma K. Persson ◽  
Noémi Nagy ◽  
...  
Keyword(s):  
T Cells ◽  
Burkitt Lymphoma ◽  
Cd4 T Cells ◽  
Epstein Barr Virus ◽  
Interleukin 4 ◽  
Nuclear Antigen ◽  
Type Ii ◽  
Signal Transducer ◽  
Barr Virus ◽  
Epstein Barr

AbstractIn line with the B-lymphotropic nature of Epstein-Barr virus (EBV), the virus is present in several types of B-cell lymphomas. EBV expresses a different set of latent genes in the associated tumors, such as EBV nuclear antigen 1 (EBNA-1) and latent membrane proteins (LMPs; type II latency) in classical Hodgkin lymphomas (HLs). We previously reported that exposure of in vitro EBV-converted, HL-derived cell line KMH2-EBV to CD40-ligand and interleukin-4 (IL-4) induced the expression of LMP-1. Here, we show that exposure to IL-4 or IL-13 alone induced LMP-1 in the absence of EBNA-2. Induction of LMP-1 by IL-4 and IL-13 was mediated by the signal transducer signal transducer and activator of transcription 6 (STAT6) and a newly defined high-affinity STAT6-binding site in the LMP-1 promoter. IL-4 induced LMP-1 also in Burkitt lymphoma–derived lines and in tonsillar B cells infected with the EBNA-2–deficient EBV strain P3HR-1. Furthermore, coculture of EBV-carrying Burkitt lymphoma cells with activated CD4+ T cells resulted in the induction of LMP-1 in the absence of EBNA-2. Because Hodgkin/Reed-Sternberg cells are known to secrete IL-13, to have constitutively activated STAT6, and to be closely surrounded by CD4+ T cells, these mechanisms may be involved in the expression of LMP-1 in EBV-positive chronic HLs.

scholarly journals Distinct memory CD4+ T-cell subsets mediate immune recognition of Epstein Barr virus nuclear antigen 1 in healthy virus carriers

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1138-1146 ◽  
Author(s):  
Kevin N. Heller ◽  
Jenica Upshaw ◽  
Beza Seyoum ◽  
Henry Zebroski ◽  
Christian Münz
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Epstein Barr Virus ◽  
T Cell Subsets ◽  
Nuclear Antigen ◽  
Effector Memory ◽  
Immune Recognition ◽  
T Helper 1 ◽  
Barr Virus ◽  
Epstein Barr

AbstractCD4+ T cells, specific for transforming latent infection with the Epstein Barr virus (EBV), consistently recognize the nuclear antigen 1 of EBV (EBNA1). EBNA1-specific effector CD4+ T cells are primarily T-helper 1 (TH1) polarized. Here we show that most healthy EBV carriers have such IFN-secreting EBNA1-specific CD4+ T cells at a frequency of 0.03% of circulating CD4+ T cells. In addition, healthy carriers have a large pool of CD4+ T cells that proliferated in response to EBNA1 and consisted of distinct memory-cell subsets. Despite continuous antigen presence due to persistent EBV infection, half of the proliferating EBNA1-specific CD4+ T cells belonged to the central-memory compartment (TCM). The remaining EBNA1-specific CD4+ T cells displayed an effector-memory phenotype (TEM), of which a minority rapidly secreted IFN upon stimulation with EBNA1. Based on chemokine receptor analysis, all EBNA1-specific TCM CD4+ T cells were TH1 committed. Our results suggest that protective immune control of chronic infections, like EBV, includes a substantial reservoir of TCM CD4+ TH1 precursors, which continuously fuels TH1-polarized effector cells.

scholarly journals Human Cd4+ T Lymphocytes Consistently Respond to the Latent Epstein-Barr Virus Nuclear Antigen Ebna1

2000 ◽  
Vol 191 (10) ◽  
pp. 1649-1660 ◽  
Author(s):  
Christian Münz ◽  
Kara L. Bickham ◽  
Marion Subklewe ◽  
Ming L. Tsang ◽  
Ann Chahroudi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Epstein Barr Virus ◽  
Cd4 T Cell ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr

The Epstein-Barr virus (EBV)-encoded nuclear antigen EBNA1 is critical for the persistence of the viral episome in replicating EBV-transformed human B cells. Therefore, all EBV-induced tumors express this foreign antigen. However, EBNA1 is invisible to CD8+ cytotoxic T lymphocytes because its Gly/Ala repeat domain prevents proteasome-dependent processing for presentation on major histocompatibility complex (MHC) class I. We now describe that CD4+ T cells from healthy adults are primed to EBNA1. In fact, among latent EBV antigens that stimulate CD4+ T cells, EBNA1 is preferentially recognized. We present evidence that the CD4+ response may provide a protective role, including interferon γ secretion and direct cytolysis after encounter of transformed B lymphocyte cell lines (B-LCLs). Dendritic cells (DCs) process EBNA1 from purified protein and from MHC class II–mismatched, EBNA1-expressing cells including B-LCLs. In contrast, B-LCLs and Burkitt's lymphoma lines likely present EBNA1 after endogenous processing, as their capacity to cross-present from exogenous sources is weak or undetectable. By limiting dilution, there is a tight correlation between the capacity of CD4+ T cell lines to recognize autologous B-LCL–expressing EBNA1 and DCs that have captured EBNA1. Therefore, CD4+ T cells can respond to the EBNA1 protein that is crucial for EBV persistence. We suggest that this immune response is initiated in vivo by DCs that present EBV-infected B cells, and that EBNA1-specific CD4+ T cell immunity be enhanced to prevent and treat EBV-associated malignancies.

scholarly journals Detection of Epstein-Barr virus-specific memory CD4+T cells using a peptide-based cultured enzyme-linked immunospot assay

Immunology ◽  
2013 ◽  
Vol 139 (4) ◽  
pp. 533-544 ◽  
Author(s):  
Sandra A. Calarota ◽  
Antonella Chiesa ◽  
Paola Zelini ◽  
Giuditta Comolli ◽  
Lorenzo Minoli ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Specific Memory ◽  
Epstein Barr ◽  
Memory Cd4 T Cells

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

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1231-1239 ◽  
Author(s):  
Cagan Gurer ◽  
Till Strowig ◽  
Fabienne Brilot ◽  
Maggi Pack ◽  
Christine Trumpfheller ◽  
...  
Keyword(s):  
T Cells ◽  
Epstein Barr Virus ◽  
Poly I:C ◽  
Nuclear Antigen ◽  
Human Immune System ◽  
Proliferating Cells ◽  
Mhc I ◽  
Barr Virus ◽  
Epstein Barr

Abstract Dendritic cells (DCs) express many endocytic receptors that deliver antigens for major histocompatibility class (MHC) I and II presentation to CD8+ and CD4+ T cells, respectively. Here, we show that targeting Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) to one of them, the human multilectin DEC-205 receptor, in the presence of the DC maturation stimulus poly(I:C), expanded EBNA1-specific CD4+ and CD8+ memory T cells, and these lymphocytes could control the outgrowth of autologous EBV-infected B cells in vitro. In addition, using a novel mouse model with reconstituted human immune system components, we demonstrated that vaccination with αDEC-205-EBNA1 antibodies primed EBNA1-specific IFN-γ–secreting T cells and also induced anti-EBNA1 antibodies in a subset of immunized mice. Because EBNA1 is the one EBV antigen that is expressed in all proliferating cells infected with this virus, our data suggest that DEC-205 targeting should be explored as a vaccination approach against symptomatic primary EBV infection and against EBV-associated malignancies.

Recovery of Functional EBV Specific T Cells Is Not Impaired In Patients with Chronic Gvhd.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1286-1286
Author(s):  
Mette Hoegh-Petersen ◽  
Yiping Liu ◽  
Stephanie Liu ◽  
Alejandra Ugarte-Torres ◽  
Kevin Fonseca ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Epstein Barr Virus ◽  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Cd8 Cells ◽  
Barr Virus ◽  
Epstein Barr

Abstract Abstract 1286 Introduction: T cell expression of PD-1, a marker of functional exhaustion manifested by inability to produce cytokines upon stimulation, is upregulated in patients with acute GHVD. This is thought to explain at least in part why patients with acute GVHD have frequent infections (Gallez-Hawkins et al, BBMT15:872, 2009). Here we wished to evaluate whether this is true also for chronic GVHD. Patients and Methods: We studied 17 allogeneic HCT recipients for AML who have not developed acute or chronic GVHD by day 84. Their blood was drawn on day 84, 180 and 365. Between day 84 and 365, 7 patients did and 10 patients did not develop chronic GVHD needing systemic immunosuppressive therapy (de novo, ie, without preceding acute GVHD). Onset of the chronic GVHD was on median day 103 (range, 90–147). We studied total CD4 and CD8 T cells as well as Epstein-Barr virus (EBV)-specific CD4 and CD8 T cells, as patients with chronic GVHD are at risk of EBV disease (Landgren et al, Blood,14:4992, 2009). Blood mononuclear cells were stimulated with Epstein-Barr virus (EBV) lysate, EBNA3A+B+C overlapping peptides, no or irrelevant stimulus as negative control, or Staphylococcal enterotoxin B as positive control. After overnight incubation, expression of IFNγ, TNFα, IL2 and PD-1 on CD3+CD4+CD8- or CD3+CD4-CD8+ cells was determined by flow cytometry. Cells expressing IFNγ, TNFα, IL2 or their combinations were enumerated. PD-1 expression was quantified using beads coated with anti-mouse antibody (Quantum Simply Cellular, Bangs Laboratories) and expressed as antibody binding capacity units (ABC) (dynamic range, approximately 300 to 500,000 ABC units per cell). Results: PD-1 expression on total, EBV lysate-specific or EBNA3-specific CD4 or CD8 T cells was not significantly higher among patients who did vs did not develop chronic GVHD. On the contrary, there was a trend toward lower PD-1 expression on EBV lysate-specific CD4 and CD8 T cells and EBNA3-specific CD4 T cells in patients who developed chronic GVHD. This was significant (p<.05, Mann-Whitney test) for EBV lysate-specific CD4 T cells on day 84, EBV lysate-specific CD8 T cells on day 180, EBV lysate-specific CD4 and CD8 T cells on day 365, EBNA3-specific CD4 T cells on day 84 and EBNA3-specific CD4 T cells on day 365. Consistent with that, absolute counts of total, EBV lysate-specific or EBNA3-specific T cells were not significantly lower in patients who did vs did not develop chronic GVHD. On the contrary, there was a trend toward higher EBV lysate-specific and EBNA3-specific CD4 or CD8 T cell counts in patients who developed chronic GVHD. This was significant on day 84 for total EBV lysate-specific CD4 and CD8 cells, EBV lysate-specific CD4+IFNγ+ cells and CD8+IFNγ+ cells, and total EBNA3-specific CD4 cells, EBNA3-specific CD4+IFNγ+ cells, CD4+IL2+ cells, CD4+IFNγ+TNFα+IL2+ cells and CD8+IFNγ+ cells. Conclusion: De novo chronic GvHD and its treatment do not adversely affect the counts of functional EBV specific T cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dendritic Cells Cross-Present Latency Gene Products from Epstein-Barr Virus–Transformed B Cells and Expand Tumor-Reactive Cd8+ Killer T Cells

2001 ◽  
Vol 193 (3) ◽  
pp. 405-412 ◽  
Author(s):  
Marion Subklewe ◽  
Casper Paludan ◽  
Ming L. Tsang ◽  
Karsten Mahnke ◽  
Ralph M. Steinman ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Class I ◽  
Nuclear Antigen ◽  
Cross Presentation ◽  
Barr Virus ◽  
Epstein Barr

Dendritic cells (DCs) are not targets for infection by the transforming Epstein-Barr virus (EBV). To test if the adjuvant role of DCs could be harnessed against EBV latency genes by cross-presentation, DCs were allowed to process either autologous or human histocompatibility leukocyte antigen (HLA)-mismatched, transformed, B lymphocyte cell lines (LCLs) that had been subject to apoptotic or necrotic cell death. After phagocytosis of small numbers of either type of dead LCL, which lacked direct immune-stimulatory capacity, DCs could expand CD8+ T cells capable of killing LCLs that were HLA matched to the DCs. Necrotic EBV-transformed, major histocompatibility complex (MHC) class I–negative LCLs, when presented by DCs, also could elicit responses to MHC class II–negative, EBV-transformed targets that were MHC class I matched to the DCs, confirming efficient cross-presentation of LCL antigens via MHC class I on the DC. Part of this EBV-specific CD8+ T cell response, in both lytic and interferon γ secretion assays, was specific for the EBV nuclear antigen (EBNA)3A and latent membrane protein (LMP)2 latency antigens that are known to be expressed at low levels in transformed cells. The induced CD8+ T cells recognized targets at low doses, 1–10 nM, of peptide. Therefore, the capacity of DCs to cross-present antigens from dead cells extends to the expansion of high affinity T cells specific for viral latency antigens involved in cell transformation.

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