TY - JOUR
T1 - Follicular Helper and Regulatory T Cells Drive the Development of Spontaneous Epstein–Barr Virus Lymphoproliferative Disorder
AU - Ahmed, Elshafa Hassan
AU - Lustberg, Mark
AU - Hale, Claire
AU - Sloan, Shelby
AU - Mao, Charlene
AU - Zhang, Xiaoli
AU - Ozer, Hatice Gulcin
AU - Schlotter, Sarah
AU - Smith, Porsha L.
AU - Jeney, Frankie
AU - Chan, Wing Keung
AU - Harrington, Bonnie K.
AU - Weigel, Christoph
AU - Brooks, Eric
AU - Klimaszewski, Haley L.
AU - Oakes, Christopher C.
AU - Abebe, Tamrat
AU - Ibrahim, Muntaser E.
AU - Alinari, Lapo
AU - Behbehani, Gregory K.
AU - Shindiapina, Polina
AU - Caligiuri, Michael A.
AU - Baiocchi, Robert A.
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
KW - CD4+ T helper subsets
KW - Epstein–Barr virus (EBV)
KW - Hu-PBL-SCID model
KW - immunocompromised patients
KW - lymphoproliferative disorder (LPD)
KW - risk factors
UR - http://www.scopus.com/inward/record.url?scp=85161936090&partnerID=8YFLogxK
U2 - 10.3390/cancers15113046
DO - 10.3390/cancers15113046
M3 - Article
AN - SCOPUS:85161936090
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 11
M1 - 3046
ER -