1. Follicular Helper and Regulatory T Cells Drive the Development of Spontaneous Epstein–Barr Virus Lymphoproliferative Disorder.
- Author
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Ahmed, Elshafa Hassan, Lustberg, Mark, Hale, Claire, Sloan, Shelby, Mao, Charlene, Zhang, Xiaoli, Ozer, Hatice Gulcin, Schlotter, Sarah, Smith, Porsha L., Jeney, Frankie, Chan, Wing Keung, Harrington, Bonnie K., Weigel, Christoph, Brooks, Eric, Klimaszewski, Haley L., Oakes, Christopher C., Abebe, Tamrat, Ibrahim, Muntaser E., Alinari, Lapo, and Behbehani, Gregory K.
- Subjects
BIOMARKERS ,CYTOKINES ,B cells ,ANIMAL experimentation ,IMMUNOCOMPROMISED patients ,REGULATORY T cells ,MYELOID-derived suppressor cells ,EPSTEIN-Barr virus ,RESEARCH funding ,LYMPHOPROLIFERATIVE disorders ,T cells ,IMMUNOLOGIC memory ,T helper cells ,MICE - Abstract
Simple Summary: Over 90% of the adult population worldwide is infected with the Epstein–Barr virus (EBV). While EBV infection is associated with the development of lymphoproliferative disorders (EBV-LPD) in people with weakened immune systems, only ~20% of immunodeficient individuals develop EBV-LPD. Such clinical heterogeneity may reflect host variables that increase the risk of developing EBV-LPD. Immunodeficient mice engrafted with blood cells from EBV+ individuals develop spontaneous EBV-LPD of human B-cell origin with similar heterogeneity observed in humans. Our study aimed to investigate differences between the model's lymphoma producers (High-Incidence, HI donors) and non-lymphoma producers (No-Incidence, NI donors). HI donors showed high levels of T follicular helper (Tfh), regulatory T cells (Treg), and myeloid-derived suppressor cells compared to NI donors. Depletion of Tfh or Treg subsets delays or prevents EBV-LPD in this model. Our results reveal potential biomarkers that may help classify vulnerable patients at risk for developing EBV-LPD. Epstein–Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a small percentage of immunocompromised patients (~20%) develop EBV-LPD. Engraftment of immunodeficient mice with peripheral blood mononuclear cells (PBMCs) from healthy EBV-seropositive donors leads to spontaneous, malignant, human B-cell EBV-LPD. Only about 20% of EBV+ donors induce EBV-LPD in 100% of engrafted mice (High-Incidence, HI), while another 20% of donors never generate EBV-LPD (No-Incidence, NI). Here, we report HI donors to have significantly higher basal T follicular helper (Tfh) and regulatory T-cells (Treg), and depletion of these subsets prevents/delays EBV-LPD. Transcriptomic analysis of CD4+ T cells from ex vivo HI donor PBMC revealed amplified cytokine and inflammatory gene signatures. HI vs. NI donors showed a marked reduction in IFNγ production to EBV latent and lytic antigen stimulation. In addition, we observed abundant myeloid-derived suppressor cells in HI donor PBMC that decreased CTL proliferation in co-cultures with autologous EBV+ lymphoblasts. Our findings identify potential biomarkers that may identify individuals at risk for EBV-LPD and suggest possible strategies for prevention. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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