Journal Article

Follicular Helper and Regulatory T Cells Drive the Development of Spontaneous Epstein–Barr Virus Lymphoproliferative Disorder

Weigel, Christoph, Ibrahim, Muntaser E., Alinari, Lapo, Hale, Claire, Ozer, Hatice Gulcin, Schlotter, Sarah, Zhang, Xiaoli, Baiocchi, Robert A., Lustberg, Mark, Shindiapina, Polina, Behbehani, Gregory K., Oakes, Christopher C., Mao, Charlene, Jeney, Frankie, Sloan, Shelby, Harrington, Bonnie K., Klimaszewski, Haley L., Smith, Porsha L., Ahmed, Elshafa Hassan, Caligiuri, Michael A., Abebe, Tamrat, Chan, Wing Keung, Brooks, Eric

2023

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Analysis / Antibodies / Antigens / Biomarkers / CD4 antigen / Cell proliferation / Cells / Cytotoxicity / Development and progression / Dimensional analysis / Disease susceptibility / Epstein-Barr virus / Genomes / Health aspects / Immunocompromised hosts / Immunodeficiency / Immunological memory / Immunoproliferative diseases / Immunoregulation / Infection / Infections / Inflammation / Latency / Leukocytes (mononuclear) / Lymphoblasts / Lymphocytes / Lymphocytes B / Lymphocytes T / Lymphoma / Lymphomas / Memory cells / Peripheral blood mononuclear cells / Proteins / Suppressor cells / T cells / Transcriptomics / Viruses / γ-Interferon