Interleukin-10 Abrogates the Inhibition of Epstein-Barr Virus–Induced B-Cell Transformation by Memory T-Cell Responses

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4256-4262 ◽  
Author(s):  
M.T. Bejarano ◽  
M.G. Masucci
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
Cell Transformation ◽  
Interleukin 10 ◽  
Barr Virus ◽  
Epstein Barr

Abstract In vitro infection of human B lymphocytes by Epstein-Barr virus (EBV) results in their growth transformation and establishment of immortalized lymphoblastoid cell lines. The virus was found to encode a homologue of the pleiotropic cytokine interleukin-10 (IL-10), which has wide-ranging effects on the immune system. We investigated the effect of human IL-10 (hIL-10) and viral IL-10 (vIL-10) on EBV-specific immunological memory, as assessed by the inhibition of EBV-induced B-cell transformation by the autologous T cells. We found that IL-10 abrogates the inhibitory capacity of T cells. This IL-10 effect is mediated through suppression of T-cell activation-induced IL-2 and interferon-γ production and through a direct enhancement of EBV-infected B-cell growth.

Interleukin-10 Abrogates the Inhibition of Epstein-Barr Virus–Induced B-Cell Transformation by Memory T-Cell Responses

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4256-4262 ◽  
Author(s):  
M.T. Bejarano ◽  
M.G. Masucci
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
Cell Transformation ◽  
Interleukin 10 ◽  
Barr Virus ◽  
Epstein Barr

In vitro infection of human B lymphocytes by Epstein-Barr virus (EBV) results in their growth transformation and establishment of immortalized lymphoblastoid cell lines. The virus was found to encode a homologue of the pleiotropic cytokine interleukin-10 (IL-10), which has wide-ranging effects on the immune system. We investigated the effect of human IL-10 (hIL-10) and viral IL-10 (vIL-10) on EBV-specific immunological memory, as assessed by the inhibition of EBV-induced B-cell transformation by the autologous T cells. We found that IL-10 abrogates the inhibitory capacity of T cells. This IL-10 effect is mediated through suppression of T-cell activation-induced IL-2 and interferon-γ production and through a direct enhancement of EBV-infected B-cell growth.

scholarly journals Analysis of the defects responsible for the impaired regulation of Epstein-Barr virus-induced B cell proliferation by rheumatoid arthritis lymphocytes. I. Diminished gamma interferon production in response to autologous stimulation.

1983 ◽  
Vol 157 (1) ◽  
pp. 173-188 ◽  
Author(s):  
F Hasler ◽  
H G Bluestein ◽  
N J Zvaifler ◽  
L B Epstein
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Gamma Interferon ◽  
Barr Virus ◽  
T Cell Regulation ◽  
Epstein Barr

T cells of patients with rheumatoid arthritis (RA) do not control the rate of B lymphoblast transformation induced by Epstein-Barr virus (EBV) as efficiently as T cells from healthy individuals; thus, lymphoblast cell lines are established more readily in RA lymphocytes in vitro after EBV infection. In the present experiments, we have asked whether this T cell regulation can be reproduced by lymphocytes. We found that normal T cells, activated in allogeneic or autologous mixed leukocyte reactions (MLR), produce lymphokines that inhibit in vitro EBV-induced B cell proliferation. Allogeneic MLR supernatants inhibited EBV-induced DNA synthesis 62 +/- 4% (mean +/- SE) at 10 d post-infection, whereas autologous MLR supernatants suppressed it 50 +/- 3%. RA T cell supernatants produced in an allogeneic MLR suppressed as well as normal T cell supernatants (64 +/- 5% inhibition). In contrast, supernatants from RA autologous MLR had little inhibitory activity. EBV-induced DNA synthesis at 10 d was reduced only 8 +/- 3%, compared with the 50 +/- 3% suppressive activity of normal autologous MLR supernatants. The magnitude of the proliferative responses in the autologous MLR regenerating the lymphokines was similar in the normal and RA populations. After depletion of adherent cells from the RA auto-MLR stimulators, supernatant inhibitory activities increased to normal levels (from 11 +/- 6 [SE] to 52 +/- 6% [SE]). The inhibitory factor involved in the regulation of in vitro EBV infection is a protein with a molecular weight of approximately 50,000. Its activity is eliminated by hearing at 56 degrees C and by exposure to acid at pH 2. The inhibitory activity is blocked by mixing the MLR supernatants with a polyvalent antisera or monoclonal antibodies specific for human gamma interferon. Gamma interferon produced by activating T cells in allo- or auto-MLR can reproduce T cell-mediated regulation of EBV-induced B cell proliferation, and the failure of RA auto-MLR to generate that lymphokine parallels the defective T cell regulation of EBV-induced B cell proliferation characteristic of RA lymphoid cells.

Transient Epstein-Barr virus reactivation in CD3 monoclonal antibody-treated patients

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1145-1155 ◽  
Author(s):  
Bart Keymeulen ◽  
Sophie Candon ◽  
Samira Fafi-Kremer ◽  
Anette Ziegler ◽  
Marianne Leruez-Ville ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
T Cell Activation ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
T Cell Response ◽  
Viral Reactivation ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Epstein Barr

Abstract Here we report a unique situation in which an early and synchronized Epstein-Barr virus (EBV) reactivation was induced by a 6-day course of treatment with a humanized CD3-specific monoclonal antibody in patients with recent onset of type 1 diabetes. The virologic and immunologic analysis demonstrated that this reactivation was transient, self-limited, and isolated, associated with the rapid advent of an EBV-specific T-cell response. The anti-CD3 antibody administration induced short-lasting immunosuppression and minor yet clear-cut signs of T-cell activation that preceded viral reactivation. Early posttransplant monitoring of renal and islet allograft recipients showed that no comparable phenomenon was observed after the administration of full-dose immunosuppressive therapy. This EBV reactivation remains of no apparent clinical concern over the long term and should not preclude further development of therapeutic anti-CD3 antibodies. This phenomenon may also direct new research avenues to understand the still ill-defined nature of stimuli triggering EBV reactivation in vivo.

scholarly journals Epstein–Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis

2013 ◽  
Vol 254 (1-2) ◽  
pp. 110-116 ◽  
Author(s):  
Emanuele Tirotta ◽  
Patrick Duncker ◽  
Jean Oak ◽  
Suzi Klaus ◽  
Michelle R. Tsukamoto ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
Barr Virus ◽  
Epstein Barr

Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 3090-3096 ◽  
Author(s):  
Huai-Chia Chuang ◽  
Jong-Ding Lay ◽  
Wen-Chuan Hsieh ◽  
Hui-Ching Wang ◽  
Yao Chang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
Hemophagocytic Syndrome ◽  
Barr Virus ◽  
Ebv Infection ◽  
Ifn Γ ◽  
Epstein Barr ◽  
Th1 Cytokines

AbstractThe primary infection of Epstein-Barr virus (EBV) may result in fatal infectious mononucleosis or hemophagocytic syndrome (HPS) in 2 diseases; that is, X-linked lymphoproliferative disorder (XLP) and hemophagocytic lymphohistiocytosis (HLH). XLP is linked to mutations of the SAP/SH2D1A gene with dysregulated T-cell activation in response to EBV infection. Patients with sporadic HLH, however, usually have no mutation of the SAP/SH2D1A gene, and EBV latent membrane protein-1 (LMP1) can up-regulate Th1 cytokines in EBV-infected T cells. Since both diseases share common manifestations of HPS, it is important to clarify whether a cross-talk exists between signaling lymphocyte activation molecule (SLAM)–associated protein (SAP) and LMP1-mediated pathways to explain the common pathogenesis of HPS. In this study, no mutation of the SAP/SH2D1A gene at exon 2/3 was detected in 7 HLH cases. Interestingly, EBV LMP1 could transcriptionally inhibit the expression of SAP/SH2D1A and activate downstream molecules ERK and interferon-γ (IFN-γ). LMP1-mediated SAP/ERK/IFN-γ signals appear to act via the TNF receptor–associated factor (TRAF)2,5/nuclear factor κB (NF-κB) pathway, since dominantnegative TRAF2/5 and NF-κB inhibitor could rescue SAP expression and downregulate IFN-γ. Although HLH is genetically distinct from XLP, our data suggest that both diseases share a common signal pathway, through either the mutation or LMP1-mediated suppression of the SAP gene, leading to overt T-cell activation and enhanced Th1 cytokine secretion in response to EBV infection.

scholarly journals 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

2002 ◽  
Vol 76 (8) ◽  
pp. 4080-4086 ◽  
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.

scholarly journals Epstein–Barr virus-induced B-cell transformation: quantitating events from virus binding to cell outgrowth

2005 ◽  
Vol 86 (11) ◽  
pp. 3009-3019 ◽  
Author(s):  
Claire Shannon-Lowe ◽  
Gouri Baldwin ◽  
Regina Feederle ◽  
Andrew Bell ◽  
Alan Rickinson ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Nucleus ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
Cell Transformation ◽  
Nuclear Antigen ◽  
Virus Binding ◽  
Barr Virus ◽  
Epstein Barr

Epstein–Barr virus (EBV) infection and growth activation of human B cells is central to virus biology and disease pathogenesis, but is poorly understood in quantitative terms. Here, using virus at defined m.o.i., the different stages of this process at the single-cell level are followed in vitro. Virus binding to the B-cell surface, assayed by quantitative PCR, is highly efficient, particularly at the low m.o.i. values that most likely reflect physiologic events in vivo. However, only 10–15 % of bound virus genomes reach the cell nucleus, as visualized by sensitive fluorescence in situ hybridization (FISH) assay; viral genomes acquired per cell nucleus range from 1 to >10, depending on the m.o.i. Thereafter, despite differences in initial genome load, almost all nuclear genome-positive cells then go on to express the virus-encoded nuclear antigen EBNA2, upregulate the cell activation antigen CD23 and transit the cell cycle. EBNA2-positive cells in the first cycle post-infection then grow out to lymphoblastoid cell lines (LCLs) just as efficiently as do cells limiting-diluted from already established LCLs. This study therefore identifies EBV genome delivery to the nucleus as a key rate-limiting step in B-cell transformation, and highlights the remarkable efficiency with which a single virus genome, having reached the nucleus, then drives the transformation programme.

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

1984 ◽  
Vol 87 (2) ◽  
pp. 646-658 ◽  
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

scholarly journals Regression of Epstein-Barr Virus-Induced B-Cell Transformation In Vitro Involves Virus-Specific CD8+ T Cells as the Principal Effectors and a Novel CD4+ T-Cell Reactivity

2005 ◽  
Vol 79 (9) ◽  
pp. 5477-5488 ◽  
Author(s):  
Nancy H. Gudgeon ◽  
Graham S. Taylor ◽  
Heather M. Long ◽  
Tracey A. Haigh ◽  
Alan B. Rickinson
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Transformation ◽  
T Cell Memory ◽  
Cell Memory ◽  
Barr Virus ◽  
Cell Clones ◽  
Epstein Barr

ABSTRACT T-cell memory to Epstein-Barr virus (EBV) was first demonstrated through regression of EBV-induced B-cell transformation to lymphoblastoid cell lines (LCLs) in virus-infected peripheral blood mononuclear cell (PBMC) cultures. Here, using donors with virus-specific T-cell memory to well-defined CD4 and CD8 epitopes, we reexamine recent reports that the effector cells mediating regression are EBV latent antigen-specific CD4+ and not, as previously assumed, CD8+ T cells. In regressing cultures, we find that the reversal of CD23+ B-cell proliferation was always coincident with an expansion of latent epitope-specific CD8+, but not CD4+, T cells; furthermore CD8+ T-cell clones derived from regressing cultures were epitope specific and reproduced regression when cocultivated with EBV-infected autologous B cells. In cultures of CD4-depleted PBMCs, there was less efficient expansion of these epitope-specific CD8+ T cells and correspondingly weaker regression. The data are consistent with an effector role for epitope-specific CD8+ T cells in regression and an auxiliary role for CD4+ T cells in expanding the CD8 response. However, we also occasionally observed late regression in CD8-depleted PBMC cultures, though again without any detectable expansion of preexisting epitope-specific CD4+ T-cell memory. CD4+ T-cell clones derived from such cultures were LCL specific in gamma interferon release assays but did not recognize any known EBV latent cycle protein or derived peptide. A subset of these clones was also cytolytic and could block LCL outgrowth. These novel effectors, whose antigen specificity remains to be determined, may also play a role in limiting virus-induced B-cell proliferation in vitro and in vivo.

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