Follicular Helper and Regulatory T Cells Drive the Development of Spontaneous Epstein-Barr Virus Lymphoproliferative Disorder.
Follicular Helper and Regulatory T Cells Drive the Development of Spontaneous Epstein-Barr Virus Lymphoproliferative Disorder.
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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.
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影响因子：
5.2
作者：
Heawchaiyaphum C;Pientong C;Yoshiyama H;Iizasa H;Panthong W;Ekalaksananan T
通讯作者：
Ekalaksananan T
影响因子：
10.1
作者：
Hartlage AS;Liu T;Patton JT;Garman SL;Zhang X;Kurt H;Lozanski G;Lustberg ME;Caligiuri MA;Baiocchi RA
通讯作者：
Baiocchi RA
DOI：
10.1126/science.1198704
发表时间：
2011-05-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bendall SC;Simonds EF;Qiu P;Amir el-AD;Krutzik PO;Finck R;Bruggner RV;Melamed R;Trejo A;Ornatsky OI;Balderas RS;Plevritis SK;Sachs K;Pe'er D;Tanner SD;Nolan GP
通讯作者：
Nolan GP
影响因子：
3.7
作者：
COLES, RE;BOYLE, TJ;LYERLY, HK
通讯作者：
LYERLY, HK
影响因子：
20.3
作者：
Dierksheide, JE;Baiocchi, RA;VanBuskirk, AM
通讯作者：
VanBuskirk, AM