scholarly journals Expansion of somatically reverted memory CD8+ T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus

2012 ◽  
Vol 209 (5) ◽  
pp. 913-924 ◽  
Author(s):  
Umaimainthan Palendira ◽  
Carol Low ◽  
Andrew I. Bell ◽  
Cindy S. Ma ◽  
Rachel J.M. Abbott ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Selective Pressure ◽  
Lymphoproliferative Disease ◽  
Effector Memory ◽  
Barr Virus ◽  
Ebv Infection ◽  
Somatic Reversion ◽  
Epstein Barr

Patients with the primary immunodeficiency X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A, are highly susceptible to Epstein-Barr virus (EBV) infection. Nonetheless, some XLP patients demonstrate less severe clinical manifestations after primary infection. SH2D1A encodes the adaptor molecule SLAM-associated protein (SAP), which is expressed in T and natural killer cells and is required for cytotoxicity against B cells, the reservoir for EBV. It is not known why the clinical presentation of XLP is so variable. In this study, we report for the first time the occurrence of somatic reversion in XLP. Reverted SAP-expressing cells resided exclusively within the CD8+ T cell subset, displayed a CD45RA−CCR7− effector memory phenotype, and were maintained at a stable level over time. Importantly, revertant CD8+ SAP+ T cells, but not SAP− cells, proliferated in response to EBV and killed EBV-infected B cells. As somatic reversion correlated with EBV infection, we propose that the virus exerts a selective pressure on the reverted cells, resulting in their expansion in vivo and host protection against ongoing infection.

scholarly journals Selective Induction of Th2-Attracting Chemokines CCL17 and CCL22 in Human B Cells by Latent Membrane Protein 1 of Epstein-Barr Virus

2004 ◽  
Vol 78 (4) ◽  
pp. 1665-1674 ◽  
Author(s):  
Takashi Nakayama ◽  
Kunio Hieshima ◽  
Daisuke Nagakubo ◽  
Emiko Sato ◽  
Masahiro Nakayama ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Epstein Barr Virus ◽  
Cytotoxic T Cells ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT Chemokines are likely to play important roles in the pathophysiology of diseases associated with Epstein-Barr virus (EBV). Here, we have analyzed the repertoire of chemokines expressed by EBV-infected B cells. EBV infection of B cells induced expression of TARC/CCL17 and MDC/CCL22, which are known to attract Th2 cells and regulatory T cells via CCR4, and also upregulated constitutive expression of MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5, which are known to attract Th1 cells and cytotoxic T cells via CCR5. Accordingly, EBV-immortalized B cells secreted these chemokines, especially CCL3, CCL4, and CCL22, in large quantities. EBV infection or stable expression of LMP1 also induced CCL17 and CCL22 in a B-cell line, BJAB. The inhibitors of the TRAF/NF-κB pathway (BAY11-7082) and the p38/ATF2 pathway (SB202190) selectively suppressed the expression of CCL17 and CCL22 in EBV-immortalized B cells and BJAB-LMP1. Consistently, transient-transfection assays using CCL22 promoter-reporter constructs demonstrated that two NF-κB sites and a single AP-1 site were involved in the activation of the CCL22 promoter by LMP1. Finally, serum CCL22 levels were significantly elevated in infectious mononucleosis. Collectively, LMP1 induces CCL17 and CCL22 in EBV-infected B cells via activation of NF-κB and probably ATF2. Production of CCL17 and CCL22, which attract Th2 and regulatory T cells, may help EBV-infected B cells evade immune surveillance by Th1 cells. However, the concomitant production of CCL3, CCL4, and CCL5 by EBV-infected B cells may eventually attract Th1 cells and cytotoxic T cells, leading to elimination of EBV-infected B cells at latency III and to selection of those with limited expression of latent genes.

scholarly journals CAR-T Cells Targeting Epstein-Barr Virus gp350 Validated in a Humanized Mouse Model of EBV Infection and Lymphoproliferative Disease

2020 ◽  
Vol 18 ◽  
pp. 504-524
Author(s):  
Constanze Slabik ◽  
Maja Kalbarczyk ◽  
Simon Danisch ◽  
Reinhard Zeidler ◽  
Frank Klawonn ◽  
...  
Keyword(s):  
T Cells ◽  
Epstein Barr Virus ◽  
Lymphoproliferative Disease ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Barr Virus ◽  
Ebv Infection ◽  
Car T Cells ◽  
Car T ◽  
Epstein Barr

Human plasmacytoid dendritic cells regulate immune responses to Epstein-Barr virus (EBV) infection and delay EBV-related mortality in humanized NOD-SCID mice

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1043-1050 ◽  
Author(s):  
Wai Hon Lim ◽  
Svjetlana Kireta ◽  
Graeme Randolph Russ ◽  
Patrick Toby Hewlett Coates
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Median Survival ◽  
Epstein Barr Virus ◽  
Lymphoproliferative Disease ◽  
Scid Mice ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV) is associated with posttransplant lymphoproliferative disease (PTLD), which is a leading cause of cancer death in recipients of transplants. We investigated the role of plasmacytoid dendritic cells (PDCs) in the development of EBV infection and the onset of lymphoproliferative disease (LPD) in humanized NOD-SCID mice and studied the effect of EBV on PDC function. NOD-SCID mice reconstituted with PDC-depleted peripheral blood mononuclear cells (PBMCs) from EBV IgG+ human donors had significantly enhanced mortality from disseminated EBV infection (median survival, 43 days) compared to PBMC-only mice (median survival, 72 days; log-rank P < .05). Mice reconstituted with PDC-enriched PBMCs challenged with EBV exhibited delayed mortality from EBV-LPD (median survival, 80 days) compared to PBMC-only mice challenged with EBV (median survival, 50 days; log-rank P < .05). EBV-stimulated pDCs produced interferon α (IFN-α) and promoted the activation of natural killer cells and IFN-γ–producing CD3+T cells. PDC activation of CD3+T cells in response to EBV stimulation was dependent on cell-to-cell contact, in part mediated by toll-like receptor 9 (TLR-9) signaling that was inhibited by chloroquine and TLR-9 inhibitory CpG. Thus, PDCs play an important role in anti-EBV cellular immune responses that may be targets for manipulation in novel strategies for the treatment of PTLD.

scholarly journals Heterogeneous Epstein-Barr virus infection patterns in peripheral T- cell lymphoma of angioimmunoblastic lymphadenopathy type

Blood ◽  
1992 ◽  
Vol 80 (7) ◽  
pp. 1804-1812 ◽  
Author(s):  
I Anagnostopoulos ◽  
M Hummel ◽  
T Finn ◽  
M Tiemann ◽  
P Korbjuhn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
Angioimmunoblastic Lymphadenopathy ◽  
Barr Virus ◽  
Ebv Infection ◽  
Infected Cells ◽  
Epstein Barr

Abstract In this study, 32 cases of T-cell lymphoma of angioimmunoblastic lymphadenopathy type (AILD-TCL) were investigated for their association with Epstein-Barr virus (EBV). For this purpose, three different approaches were applied: polymerase chain reaction (PCR) for the presence of EBV-DNA, in situ hybridization (ISH) for EBV-encoded small nuclear RNAs (EBER), and immunohistology for EBV-encoded latent membrane protein (LMP). PCR and EBER-ISH produced almost identical results, showing that all but one case of AILD-TCL contained EBV genomes. Three distinctive patterns of EBV infection were observed after immunophenotypical characterization of EBER-positive cells: (1) in 26% of the cases, B and T cells were infected, the majority of which were B cells of immunoblastic morphology located in the remnants of lymphoid follicles; (2) in 42% of the cases, the vast majority of infected cells were neoplastic T cells diffusely distributed in the lymph nodes, but infected B cells were also present; and (3) in 32% of the cases, there were only a few infected small lymphoid cells. Detectable LMP was frequent in cases exhibiting patterns 1 and 2. These findings suggest that in AILD-TCL patients, B cells and especially T cells are highly susceptible to a persistent EBV infection, which often leads to a growth advantage of the infected cells. Thus EBV, in conjunction with genetic abnormalities and selective defects of the immune system, might be involved in the pathogenesis of AILD-TCL.

scholarly journals Lytic Induction Therapy for Epstein-Barr Virus-Positive B-Cell Lymphomas

2004 ◽  
Vol 78 (4) ◽  
pp. 1893-1902 ◽  
Author(s):  
Wen-hai Feng ◽  
Gregory Hong ◽  
Henri-Jacques Delecluse ◽  
Shannon C. Kenney
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Lymphoproliferative Disease ◽  
Immediate Early ◽  
B Cell Lymphomas ◽  
Lymphoblastoid Cells ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT A novel therapy for Epstein-Barr virus (EBV)-positive tumors involves the intentional induction of the lytic form of EBV infection combined with ganciclovir (GCV) treatment. Virally encoded kinases (thymidine kinase and BGLF4) which are expressed only during the lytic form of infection convert GCV (a nucleoside analogue) into its active, cytotoxic form. However, tightly latent EBV infection in B cells has made it difficult to identify drugs that can be used clinically to induce lytic viral infection in B-cell lymphomas. Here we demonstrate that gemcitabine and doxorubicin (but not 5-azacytidine, cis-platinum, or 5-fluorouracil) induce lytic EBV infection in EBV-transformed B cells in vitro and in vivo. Gemcitabine and doxorubicin both activated transcription from the promoters of the two viral immediate-early genes, BZLF1 and BRLF1, in EBV-negative B cells. This effect required the EGR-1 motif in the BRLF1 promoter and the CRE (ZII) and MEF-2D (ZI) binding sites in the BZLF1 promoter. GCV enhanced cell killing by gemcitabine or doxorubicin in lymphoblastoid cells transformed with wild-type EBV, but not in lymphoblastoid cells transformed by a mutant virus (with a deletion in the BZLF1 immediate-early gene) that is unable to enter the lytic form of infection. Most importantly, the combination of gemcitabine or doxorubicin and GCV was significantly more effective for the inhibition of EBV-driven lymphoproliferative disease in SCID mice than chemotherapy alone. In contrast, the combination of zidovudine and gemcitabine was no more effective than gemcitabine alone. These results suggest that the addition of GCV to either gemcitabine- or doxorubicin-containing chemotherapy regimens may enhance the therapeutic efficacy of these drugs for EBV-driven lymphoproliferative disease in patients.

scholarly journals Inherited CD70 deficiency in humans reveals a critical role for the CD70–CD27 pathway in immunity to Epstein-Barr virus infection

2016 ◽  
Vol 214 (1) ◽  
pp. 73-89 ◽  
Author(s):  
Kazushi Izawa ◽  
Emmanuel Martin ◽  
Claire Soudais ◽  
Julie Bruneau ◽  
David Boutboul ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Critical Role ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Cell Proliferations

Epstein-Barr virus (EBV) infection in humans is a major trigger of malignant and nonmalignant B cell proliferations. CD27 is a co-stimulatory molecule of T cells, and inherited CD27 deficiency is characterized by high susceptibility to EBV infection, though the underlying pathological mechanisms have not yet been identified. In this study, we report a patient suffering from recurrent EBV-induced B cell proliferations including Hodgkin’s lymphoma because of a deficiency in CD70, the ligand of CD27. We show that EBV-specific T lymphocytes did not expand properly when stimulated with CD70-deficient EBV-infected B cells, whereas expression of CD70 in B cells restored expansion, indicating that CD70 on B cells but not on T cells is required for efficient proliferation of T cells. CD70 was found to be up-regulated on B cells when activated and during EBV infection. The proliferation of T cells triggered by CD70-expressing B cells was dependent on CD27 and CD3 on T cells. Importantly, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells. Thus, the CD70–CD27 pathway appears to be a crucial component of EBV-specific T cell immunity and more generally for the immune surveillance of B cells and may be a target for immunotherapy of B cell malignancies.

scholarly journals Heterogeneous Epstein-Barr virus infection patterns in peripheral T- cell lymphoma of angioimmunoblastic lymphadenopathy type

Blood ◽  
1992 ◽  
Vol 80 (7) ◽  
pp. 1804-1812 ◽  
Author(s):  
I Anagnostopoulos ◽  
M Hummel ◽  
T Finn ◽  
M Tiemann ◽  
P Korbjuhn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
Angioimmunoblastic Lymphadenopathy ◽  
Barr Virus ◽  
Ebv Infection ◽  
Infected Cells ◽  
Epstein Barr

In this study, 32 cases of T-cell lymphoma of angioimmunoblastic lymphadenopathy type (AILD-TCL) were investigated for their association with Epstein-Barr virus (EBV). For this purpose, three different approaches were applied: polymerase chain reaction (PCR) for the presence of EBV-DNA, in situ hybridization (ISH) for EBV-encoded small nuclear RNAs (EBER), and immunohistology for EBV-encoded latent membrane protein (LMP). PCR and EBER-ISH produced almost identical results, showing that all but one case of AILD-TCL contained EBV genomes. Three distinctive patterns of EBV infection were observed after immunophenotypical characterization of EBER-positive cells: (1) in 26% of the cases, B and T cells were infected, the majority of which were B cells of immunoblastic morphology located in the remnants of lymphoid follicles; (2) in 42% of the cases, the vast majority of infected cells were neoplastic T cells diffusely distributed in the lymph nodes, but infected B cells were also present; and (3) in 32% of the cases, there were only a few infected small lymphoid cells. Detectable LMP was frequent in cases exhibiting patterns 1 and 2. These findings suggest that in AILD-TCL patients, B cells and especially T cells are highly susceptible to a persistent EBV infection, which often leads to a growth advantage of the infected cells. Thus EBV, in conjunction with genetic abnormalities and selective defects of the immune system, might be involved in the pathogenesis of AILD-TCL.

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