scholarly journals Absence of allogeneic restriction in human T-cell-mediated cytotoxicity to Epstein-Barr virus-infected target cells. Demonstration of an HLA-linked control at the effector level.

1979 ◽  
Vol 150 (6) ◽  
pp. 1310-1322 ◽  
Author(s):  
M Lipinski ◽  
W H Fridman ◽  
T Tursz ◽  
C Vincent ◽  
D Pious ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cell Surface ◽  
Target Cell ◽  
Epstein Barr Virus ◽  
Target Cells ◽  
Specific Lysis ◽  
Barr Virus ◽  
Positive Target ◽  
Epstein Barr

Peripheral T lymphocytes from patients with infectious mononucleosis (IM) are sensitized in vivo against the Epstein-Barr virus (EBV). The expression of HLA-A, B, or C molecules at the target cell surface is necessary for the cytotoxic reaction because (a) EBV-positive Daudi cells lacking HLA-A, B, and C determinants are resistant to anti-EBV T-cell lysis, (b) cytolysis of EBV-positive target cells can be consistently inhibited by anti-HLA-A, B, and C and anti-beta 2 microglobulin antibodies. However, no evidence for allogeneic restriction in this system was apparent as (a) cytotoxic T lymphocytes (CTL) from one given individual could exert a cytotoxicity of a similar magnitude on different EBV-positive target cells, regardless of the number of HLA-A or B specificities shared by the effectors and targets; (b) CTL from IM patients were able to kill target cells without any HLA-A or B antigen in common; and (c) T5-1 variants lacking one or two HLA antigens at the A, B, or D locus are killed to the same extent as the parental cells. 7 of the 9 IM patients with detectable circulating anti-EBV CTL carried the HLA-A1 antigen, whereas none of the 16 IM patients lacking detectable peripheral CTL were HLA-A1 positive (mean specific lysis of T5-1 target cells by T cells from HLA-A1 positive patients: 29.3 vs. 0.6% in HLA-A1-negative patients) (P less than 10(-9)). These data suggest an HLA-A1-linked gene control of the magnitude of the anti-EBV CTL response. Thus, the HLA region appears to act at two different level sin the T-cell-mediated lysis of EBV-infected cells by controlling first, the development of anti-EBV and second, the expression of HLA-A, B, and C molecules involved as recognition structures at the target cell surface.

scholarly journals CAR-T cells and TRUCKs that recognize an EBNA-3C-derived epitope presented on HLA-B*35 control Epstein-Barr virus-associated lymphoproliferation

2020 ◽  
Vol 8 (2) ◽  
pp. e000736
Author(s):  
Anna Christina Dragon ◽  
Katharina Zimmermann ◽  
Thomas Nerreter ◽  
Deborah Sandfort ◽  
Julia Lahrberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Immune Cells ◽  
Epstein Barr Virus ◽  
Target Cells ◽  
Barr Virus ◽  
Car T Cells ◽  
Car T ◽  
Epstein Barr

BackgroundImmunosuppressive therapy or T-cell depletion in transplant patients can cause uncontrolled growth of Epstein-Barr virus (EBV)-infected B cells resulting in post-transplant lymphoproliferative disease (PTLD). Current treatment options do not distinguish between healthy and malignant B cells and are thereby often limited by severe side effects in the already immunocompromised patients. To specifically target EBV-infected B cells, we developed a novel peptide-selective chimeric antigen receptor (CAR) based on the monoclonal antibody TÜ165 which recognizes an Epstein-Barr nuclear antigen (EBNA)−3C-derived peptide in HLA-B*35 context in a T-cell receptor (TCR)-like manner. In order to attract additional immune cells to proximity of PTLD cells, based on the TÜ165 CAR, we moreover generated T cells redirected for universal cytokine-mediated killing (TRUCKs), which induce interleukin (IL)-12 release on target contact.MethodsTÜ165-based CAR-T cells (CAR-Ts) and TRUCKs with inducible IL-12 expression in an all-in-one construct were generated. Functionality of the engineered cells was assessed in co-cultures with EBNA-3C-peptide-loaded, HLA-B*35-expressing K562 cells and EBV-infected B cells as PTLD model. IL-12, secreted by TRUCKs on target contact, was further tested for its chemoattractive and activating potential towards monocytes and natural killer (NK) cells.ResultsAfter co-cultivation with EBV target cells, TÜ165 CAR-Ts and TRUCKs showed an increased activation marker expression (CD137, CD25) and release of proinflammatory cytokines (interferon-γ and tumor necrosis factor-α). Moreover, TÜ165 CAR-Ts and TRUCKs released apoptosis-inducing mediators (granzyme B and perforin) and were capable to specifically lyse EBV-positive target cells. Live cell imaging revealed a specific attraction of TÜ165 CAR-Ts around EBNA-3C-peptide-loaded target cells. Of note, TÜ165 TRUCKs with inducible IL-12 showed highly improved effector functions and additionally led to recruitment of monocyte and NK cell lines.ConclusionsOur results demonstrate that TÜ165 CAR-Ts recognize EBV peptide/HLA complexes in a TCR-like manner and thereby allow for recognizing an intracellular EBV target. TÜ165 TRUCKs equipped with inducible IL-12 expression responded even more effectively and released IL-12 recruited additional immune cells which are generally missing in proximity of lymphoproliferation in immunocompromised PTLD patients. This suggests a new and promising strategy to specifically target EBV-infected cells while sparing and mobilizing healthy immune cells and thereby enable control of EBV-associated lymphoproliferation.

Su.35. Epstein-Barr Virus Downregulates B Cell Surface CD1d to Evade Natural Killer T Cell Detection

2008 ◽  
Vol 127 ◽  
pp. S135-S136 ◽  
Author(s):  
Brian Chung ◽  
Lenka Allan ◽  
Dong Jun Zheng ◽  
John Priatel ◽  
Peter van den Elzen ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
B Cell ◽  
Natural Killer ◽  
Epstein Barr Virus ◽  
Cell Detection ◽  
Natural Killer T Cell ◽  
Barr Virus ◽  
Epstein Barr ◽  
Killer T Cell

scholarly journals Model of Epstein-Barr virus infection of human thymocytes: expression of viral genome and impact on cellular receptor expression in the T- lymphoblastic cell line, HPB-ALL

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 456-464 ◽  
Author(s):  
RL Paterson ◽  
C Kelleher ◽  
TD Amankonah ◽  
JE Streib ◽  
JW Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Cell Line ◽  
Epstein Barr Virus ◽  
Receptor Expression ◽  
Productive Infection ◽  
Epithelial Tissue ◽  
Cellular Receptor ◽  
Barr Virus ◽  
Epstein Barr

Infection of B lymphocytes and epithelial tissue by Epstein-Barr virus (EBV) is associated with malignancy and autoimmunity. The cellular receptor for EBV has been identified as CD21 (CR2). A molecule, which is biochemically and immunologically similar to B-cell CD21, has been identified on a subpopulation of immature thymocytes, suggesting a role for this molecule in the regulation of T-cell development and further suggesting that immature T cells might be susceptible to EBV infection. A growing body of literature now documents the presence of EBV in tumors of T-cell origin. We have evaluated the susceptibility of the human immature T cell line, HPB-ALL, to infection by EBV. Electron microscopy studies showed a rapid internalization of virus by HPB cells. Southern blotting showed the intracellular presence of linear EBV genomes, and components of the virus replicative cycle were identified. Expression of the BamHI Z region of the genome, encoding the nuclear protein, ZEBRA, which is strictly associated with productive infection in B cells, was detected in HPB-ALL cells. A spliced variant of Z, RAZ, was also identified. Cell surface expression of EBV late antigens was observed to occur transiently. Infection of HPB cells was also accompanied by altered expression of T-cell surface molecules involved in antigen recognition, a process critical to normal development of the T-cell repertoire. Delineation of the outcome of T- cell infection by EBV may lead to a better understanding of the role of this virus in autoimmune processes and malignancy.

scholarly journals CD4+ T-Cell Responses to Epstein-Barr Virus Nuclear Antigen EBNA1 in Chinese Populations Are Highly Focused on Novel C-Terminal Domain-Derived Epitopes

2006 ◽  
Vol 80 (16) ◽  
pp. 8263-8266 ◽  
Author(s):  
C. W. Tsang ◽  
X. Lin ◽  
N. H. Gudgeon ◽  
G. S. Taylor ◽  
H. Jia ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
T Cell Responses ◽  
Nuclear Antigen ◽  
Target Cells ◽  
Chinese Populations ◽  
Barr Virus ◽  
Cell Responses ◽  
Epstein Barr ◽  
The One

ABSTRACT Epstein-Barr virus nuclear antigen EBNA1, the one viral protein uniformly expressed in nasopharyngeal carcinoma (NPC), represents a prime target for T-cell-based immunotherapy. However, little is known about the EBNA1 epitopes, particularly CD4 epitopes, presented by HLA alleles in Chinese people, the group at highest risk for NPC. We analyzed the CD4+ T-cell responses to EBNA1 in 78 healthy Chinese donors and found marked focusing on a small number of epitopes in the EBNA1 C-terminal region, including a DP5-restricted epitope that was recognized by almost half of the donors tested and elicited responses able to recognize EBNA1-expressing, DP5-positive target 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 Epstein Barr Virus: Development of Vaccines and Immune Cell Therapy for EBV-Associated Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Xinle Cui ◽  
Clifford M. Snapper
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Neutralizing Antibodies ◽  
Epstein Barr Virus ◽  
Immune Cell ◽  
Critical Role ◽  
Target Cells ◽  
T Cell Therapy ◽  
Barr Virus ◽  
Epstein Barr

Epstein-Barr virus (EBV) is the first human tumor virus discovered and is strongly implicated in the etiology of multiple lymphoid and epithelial cancers. Each year EBV associated cancers account for over 200,000 new cases of cancer and cause 150,000 deaths world-wide. EBV is also the primary cause of infectious mononucleosis, and up to 70% of adolescents and young adults in developed countries suffer from infectious mononucleosis. In addition, EBV has been shown to play a critical role in the pathogenesis of multiple sclerosis. An EBV prophylactic vaccine that induces neutralizing antibodies holds great promise for prevention of EBV associated diseases. EBV envelope proteins including gH/gL, gB and gp350 play key roles in EBV entry and infection of target cells, and neutralizing antibodies elicited by each of these proteins have shown to prevent EBV infection of target cells and markedly decrease EBV titers in the peripheral blood of humanized mice challenged with lethal dose EBV. Recent studies demonstrated that immunization with the combination of gH/gL, gB and/or gp350 induced markedly increased synergistic EBV neutralizing activity compared to immunization with individual proteins. As previous clinical trials focused on gp350 alone were partially successful, the inclusion of gH/gL and gB in a vaccine formulation with gp350 represents a promising approach of EBV prophylactic vaccine development. Therapeutic EBV vaccines have also been tested clinically with encouraging results. Immunization with various vaccine platforms expressing the EBV latent proteins EBNA1, LMP1, and/or LMP2 promoted specific CD4+ and CD8+ cytotoxic responses with anti-tumor activity. The addition of EBV envelope proteins gH/gL, gB and gp350 has the potential to increase the efficacy of a therapeutic EBV vaccine. The immune system plays a critical role in the control of tumors, and immune cell therapy has emerged as a promising treatment of cancers. Adoptive T-cell therapy has been successfully used in the prevention and treatment of post-transplant lymphoproliferative disorder. Chimeric antigen receptor T cell therapy and T cell receptor engineered T cell therapy targeting EBV latent proteins LMP1, LMP2 and/or EBNA1 have been in development, with the goal to increase the specificity and efficacy of treatment of EBV associated cancers.

scholarly journals Cytolytic mechanisms and T-cell receptor Vβ usage byex vivogenerated Epstein-Barr virus-specific cytotoxic T lymphocytes

Immunology ◽  
2009 ◽  
Vol 127 (4) ◽  
pp. 577-586 ◽  
Author(s):  
Victoria J. Vanhoutte ◽  
Karen A. McAulay ◽  
Erin McCarrell ◽  
Marc Turner ◽  
Dorothy H. Crawford ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
Cytotoxic T Lymphocytes ◽  
Epstein Barr Virus ◽  
Cell Receptor ◽  
Barr Virus ◽  
Epstein Barr ◽  
T Cell Receptor Vβ

scholarly journals Impaired Epstein-Barr virus–specific CD8+ T-cell function in X-linked lymphoproliferative disease is restricted to SLAM family–positive B-cell targets

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3249-3257 ◽  
Author(s):  
Andrew D. Hislop ◽  
Umaimainthan Palendira ◽  
Alison M. Leese ◽  
Peter D. Arkwright ◽  
Pierre S. Rohrlich ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Lymphoproliferative Disease ◽  
Target Cells ◽  
Barr Virus ◽  
Ebv Infection ◽  
Slam Family ◽  
Epstein Barr

Abstract X-linked lymphoproliferative disease (XLP) is a condition associated with mutations in the signaling lymphocytic activation molecule (SLAM)–associated protein (SAP; SH2D1A). SAP functions as an adaptor, binding to and recruiting signaling molecules to SLAM family receptors expressed on T and natural killer cells. XLP is associated with extreme sensitivity to primary Epstein-Barr virus (EBV) infection, often leading to a lethal infectious mononucleosis. To investigate EBV-specific immunity in XLP patients, we studied 5 individuals who had survived EBV infection and found CD8+ T-cell responses numerically comparable with healthy donors. However, further investigation of in vitro–derived CD8+ T-cell clones established from 2 of these donors showed they efficiently recognized SLAM ligand–negative target cells expressing EBV antigens, but showed impaired recognition of EBV-transformed, SLAM ligand–positive, lymphoblastoid cell lines (LCLs). Importantly, LCL recognition was restored when interactions between the SLAM receptors CD244 and natural killer–, T-, and B-cell antigen (NTBA) and their ligands on LCLs were blocked. We propose that XLP patients' particular sensitivity to EBV, and not to other viruses, reflects at least in part EBV's strict tropism for B lymphocytes and the often inability of the CD8+ T-cell response to contain the primary infection of SLAM ligand–expressing target cells.

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