Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells

Infection of T cells by Epstein-Barr virus (EBV) causes chronic active EBV infection (CAEBV) characterized by T cell lymphoproliferative disorders (T-LPD) of unclear etiology. Here, we identified two homozygous biallelic loss-of-function mutations in PIK3CD and TNFRSF9 in a patient who developed a fatal CAEBV. The mutation in TNFRSF9 gene coding CD137/4-1BB, a costimulatory molecule expressed by antigen-specific activated T cells, resulted in a complete loss of CD137 expression and impaired T cell expansion toward CD137 ligand–expressing cells. Isolated as observed in one sibling, CD137 deficiency resulted in persistent EBV-infected T cells but without clinical manifestations. The mutation in PIK3CD gene that encodes the catalytic subunit p110δ of the PI3K significantly reduced its kinase activity. Deficient T cells for PIK3CD exhibited reduced AKT signaling, while calcium flux, RAS-MAPK activation, and proliferation were increased, suggestive of an imbalance between the PLCγ1 and PI3K pathways. These skewed signals in T cells may sustain accumulation of EBV-infected T cells, a process controlled by the CD137–CD137L pathway, highlighting its critical role in immunity to EBV.

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Redirecting T Cells against Epstein–Barr Virus Infection and Associated Oncogenesis

Cells ◽

10.3390/cells9061400 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1400 ◽

Cited By ~ 1

Author(s):

Christian Münz

Keyword(s):

T Cells ◽

T Cell ◽

Epstein Barr Virus ◽

Clinical Success ◽

Viral Gene ◽

Epstein Barr Virus Infection ◽

Antigen Receptors ◽

Transgenic Expression ◽

Barr Virus ◽

Epstein Barr

The Epstein–Barr virus (EBV) is associated with lymphomas and carcinomas. For some of these, the adoptive transfer of EBV specific T cells has been therapeutically explored, with clinical success. In order to avoid naturally occurring EBV specific autologous T cell selection from every patient, the transgenic expression of latent and early lytic viral antigen specific T cell receptors (TCRs) to redirect T cells, to target the respective tumors, is being developed. Recent evidence suggests that not only TCRs against transforming latent EBV antigens, but also against early lytic viral gene products, might be protective for the control of EBV infection and associated oncogenesis. At the same time, these approaches might be more selective and cause less collateral damage than targeting general B cell markers with chimeric antigen receptors (CARs). Thus, EBV specific TCR transgenic T cells constitute a promising therapeutic strategy against EBV associated malignancies.

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Primary Epstein-Barr virus infection does not erode preexisting CD8+ T cell memory in humans

Journal of Experimental Medicine ◽

10.1084/jem.20112401 ◽

2012 ◽

Vol 209 (3) ◽

pp. 471-478 ◽

Cited By ~ 45

Author(s):

Oludare A. Odumade ◽

Jennifer A. Knight ◽

David O. Schmeling ◽

David Masopust ◽

Henry H. Balfour ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Epstein Barr Virus ◽

Cd8 T Cell ◽

T Cell Response ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr

Acute Epstein-Barr virus (EBV) infection results in an unusually robust CD8+ T cell response in young adults. Based on mouse studies, such a response would be predicted to result in attrition of preexisting memory to heterologous infections like influenza A (Flu) and cytomegalovirus (CMV). Furthermore, many studies have attempted to define the lymphocytosis that occurs during acute EBV infection in humans, but it is unclear whether bystander T cells contribute to it. To address these issues, we performed a longitudinal prospective study of primary EBV infection in humans. During acute EBV infection, both preexisting CMV- and Flu-specific memory CD8+ T cells showed signs of bystander activation, including up-regulation of granzyme B. However, they generally did not expand, suggesting that the profound CD8+ lymphocytosis associated with acute EBV infection is composed largely of EBV-specific T cells. Importantly, the numbers of CMV- and Flu-specific T cells were comparable before and after acute EBV infection. The data support the concept that, in humans, a robust CD8+ T cell response creates a new memory CD8+ T cell niche without substantially depleting preexisting memory for heterologous infections.

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

Journal of Experimental Medicine ◽

10.1084/jem.20160784 ◽

2016 ◽

Vol 214 (1) ◽

pp. 73-89 ◽

Cited By ~ 68

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.

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Preferential Expansion of Vγ9-JγP/Vδ2-Jδ3 γδ T Cells in Nasal T-Cell Lymphoma and Chronic Active Epstein-Barr Virus Infection

American Journal Of Pathology ◽

10.1016/s0002-9440(10)64297-6 ◽

2003 ◽

Vol 162 (5) ◽

pp. 1629-1638 ◽

Cited By ~ 18

Author(s):

Michiko K. Oyoshi ◽

Hiroshi Nagata ◽

Nobuhiro Kimura ◽

Yu Zhang ◽

Ayako Demachi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Infection ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

Γδ T Cells ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Epstein Barr ◽

Barr Virus Infection

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Peripheral T-cell Lymphoma, NOS With Epstein-Barr Virus Positivity in an Elderly Patient With Myelodysplastic Syndrome: An Autopsy Case Report

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa161.178 ◽

2020 ◽

Vol 154 (Supplement_1) ◽

pp. S81-S81

Author(s):

J Lanceta ◽

W Xue ◽

M Hurford ◽

H Wu

Keyword(s):

Bone Marrow ◽

T Cells ◽

Lymph Node ◽

T Cell ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Barr Virus ◽

Epstein Barr

Abstract Casestudy Epstein-Barr virus (EBV)-associated peripheral T-cell lymphomas are a group of aggressive neoplasms with a geographic predilection for South America and Asia, but are very rare in Western populations. Results We report a case of a 74-year-old Caucasian female who presented with pancytopenia and B symptoms with EBV-IgG detected on admission. Past medical history included: ITP, chronic urticaria, and recently diagnosed myelodysplastic syndrome (MDS) on bone marrow biopsy one month prior to admission. Excisional biopsies of an enlarged right neck lymph node (repeated within 6 months) and right axillary lymph node five years ago were negative for a lymphoproliferative disorder at the time. Repeated bone marrow biopsy, performed during the current admission, confirmed the diagnosis of MDS, with scattered T-cells without aberrant immunophenotype. Despite aggressive treatment from multiple specialties, the patient deteriorated and expired four weeks later from complications of MDS. At autopsy, there was diffuse lymphadenopathy involving the mediastinum, axilla, pelvis and peripancreatic fat. Lymph node sections demonstrated nodal architecture effacement by diffuse, vaguely nodular lymphoid infiltrates. Histologically, the infiltrates were composed of medium to large lymphocytes with round to slight irregular nuclei, rare Reed-Sternberg-like multinucleated cells, clumped chromatin, and indistinct nucleoli. Individual cell necrosis was abundant with mitotic figures readily identifiable. Immunohistochemistry revealed CD2+ CD3+ neoplastic T-cells that co-express MUM1 and a subset of CD30, while negative for CD4, CD5, CD8, CD56, ALK1, and TDT. EBV-encoded RNA in-situ hybridization was focally positive. The final postmortem diagnosis was peripheral T-cell lymphoma, not otherwise specified (NOS), with focal EBV positivity. Conclusion Co-existence of a de-novo MDS and non-Hodgkin lymphoma without any prior chemotherapeutic exposure is a highly unusual finding, although MDS-like presentations can occur with EBV-associated lymphomas. Peripheral T-cell lymphoma, NOS is an aggressive lymphoma and EBV positivity has been found correlated with a poor prognosis. This case demonstrates how postmortem examination remains an important tool in clinical- pathological correlation and highlights the potential pathogenetic role EBV plays in MDS and T-cell lymphoma.

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The latency pattern of Epstein–Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas

British Journal of Cancer ◽

10.1054/bjoc.2000.1687 ◽

2001 ◽

Vol 84 (7) ◽

pp. 920-925 ◽

Cited By ~ 32

Author(s):

Z-G Xu ◽

K Iwatsuki ◽

N Oyama ◽

M Ohtsuka ◽

M Satoh ◽

...

Keyword(s):

T Cell ◽

Virus Infection ◽

Epstein Barr Virus ◽

Epstein Barr Virus Infection ◽

Natural Killer T Cell ◽

Barr Virus ◽

T Cell Lymphomas ◽

Epstein Barr ◽

Barr Virus Infection ◽

Killer T Cell

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Infusion of Cytotoxic T Cells for the Prevention and Treatment of Epstein-Barr Virus–Induced Lymphoma in Allogeneic Transplant Recipients

Blood ◽

10.1182/blood.v92.5.1549 ◽

1998 ◽

Vol 92 (5) ◽

pp. 1549-1555 ◽

Cited By ~ 834

Author(s):

Cliona M. Rooney ◽

Colton A. Smith ◽

Catherine Y.C. Ng ◽

Susan K. Loftin ◽

John W. Sixbey ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Epstein Barr Virus ◽

Mononuclear Cells ◽

Cytotoxic T Cells ◽

Marker Gene ◽

Barr Virus ◽

Immunoblastic Lymphoma ◽

Epstein Barr ◽

T Cell Lines

Abstract Epstein-Barr virus (EBV) causes potentially lethal immunoblastic lymphoma in up to 25% of children receiving bone marrow transplants from unrelated or HLA-mismatched donors. Because this complication appears to stem from a deficiency of EBV-specific cytotoxic T cells, we assessed the safety and efficacy of donor-derived polyclonal (CD4+ and CD8+) T-cell lines as immunoprophylaxis and treatment for EBV-related lymphoma. Thirty-nine patients considered to be at high risk for EBV-induced lymphoma each received 2 to 4 intravenous infusions of donor-derived EBV-specific T lymphocytes, after they had received T-cell–depleted bone marrow from HLA-matched unrelated donors (n = 33) or mismatched family members (n = 6). The immunologic effects of this therapy were monitored during and after the infusions. Infused cells were identified by detection of the neo marker gene. EBV-specific T cells bearing theneo marker were identified in all but 1 of the patients. Serial analysis of DNA detected the marker gene for as long as 18 weeks in unmanipulated peripheral blood mononuclear cells and for as long as 38 months in regenerated lines of EBV-specific cytotoxic T cells. Six patients (15.5%) had greatly increased amounts of EBV-DNA on study entry (>2,000 genome copies/106 mononuclear cells), indicating uncontrolled EBV replication, a complication that has had a high correlation with subsequent development of overt lymphoma. All of these patients showed 2 to 4 log decreases in viral DNA levels within 2 to 3 weeks after infusion and none developed lymphoma, confirming the antiviral activity of the donor-derived cells. There were no toxic effects that could be attributed to prophylactic T-cell therapy. Two additional patients who did not receive prophylaxis and developed overt immunoblastic lymphoma responded fully to T-cell infusion. Polyclonal donor-derived T-cell lines specific for EBV proteins can thus be used safely to prevent EBV-related immunoblastic lymphoma after allogeneic marrow transplantation and may also be effective in the treatment of established disease. © 1998 by The American Society of Hematology.

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