Characterizing EBV-associated lymphoproliferative diseases and the role of myeloid-derived suppressor cells
Characterizing EBV-associated lymphoproliferative diseases and the role of myeloid-derived suppressor cells
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DOI：
10.1182/blood.2020005611
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发表时间：
2021-01-14
期刊：
影响因子：
20.3
通讯作者：
Shannon-Lowe, Claire
中科院分区：
文献类型：
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作者：
Collins, Paul J.;Fox, Christopher P.;Shannon-Lowe, Claire
慢性活动性EB病毒（CAEBV）通常表现为持续性感染性单核细胞增多症样疾病和/或噬血细胞淋巴组织细胞增多症（HLH），反映了异位EB病毒（EBV）感染和T细胞和/或NK细胞的淋巴增殖。临床表现范围从无痛、稳定的疾病到快速进展、危及生命的疾病。虽然认为慢性和/或进展反映了免疫控制的逃避，但对感染细胞与共存的未感染群体的表型和功能知之甚少，也不知道可能支持其逃避宿主免疫监视的机制。为了研究这些问题，我们开发了一种结合表型和功能标记物染色与原位杂交的EB病毒编码的RNA（EBER）在每个感染的细胞中表达的流式细胞术技术。这允许对患者血液样品中感染的（EBERPOS）和未感染的（EBERNEG）淋巴细胞亚群进行离体鉴定、表型分析和功能比较。我们用离散的EBV激活的T细胞亚群的单克隆群体表征了CAEBV和HLH病例，在某些情况下伴有EBV激活的NK细胞亚群，尽管有标准的基于类固醇的治疗，但感染细胞进展的纵向数据。考虑到在最佳研究患者的血液中可检测到具有相关EBV抗原特异性的细胞毒性CD8（+）T细胞，我们寻找可能损害宿主监测的方法。这揭示了几乎每个研究的CAEBV患者的独特特征：存在大量骨髓来源的抑制细胞，这些细胞表现出对T细胞生长的强烈抑制。我们认为，它们的影响可能解释宿主未能包含EBV阳性T/NK细胞增殖。
Chronic active Epstein-Barr virus (CAEBV) typically presents as persistent infectious mononucleosis-like disease and/or hemophagocytic lymphohistocytosis (HLH), reflecting ectopic Epstein-Barr virus (EBV) infection and lymphoproliferation of T and/or NK cells. Clinical behavior ranges from indolent, stable disease through to rapidly progressive, life-threatening disease. Although it is thought the chronicity and/or progression reflect an escape from immune control, very little is known about the phenotype and function of the infected cells vs coresident noninfected population, nor about the mechanisms that could underpin their evasion of host immune surveillance. To investigate these questions, we developed a multicolor flow cytometry technique combining phenotypic and functional marker staining with in situ hybridization for the EBV-encoded RNAs (EBERs) expressed in every infected cell. This allows the identification, phenotyping, and functional comparison of infected (EBERPOS) and noninfected (EBERNEG) lymphocyte subset(s) in patients' blood samples ex vivo. We have characterized CAEBV and HLH cases with monoclonal populations of discrete EBV-activated T-cell subsets, in some cases accompanied by EBV-activated NK-cell subsets, with longitudinal data on the infected cells' progression despite standard steroid-based therapy. Given that cytotoxic CD8(+) T cells with relevant EBV antigen specificity were detectable in the blood of the best studied patient, we searched for means whereby host surveillance might be impaired. This revealed a unique feature in almost every patient with CAEBV studied: the presence of large numbers of myeloid-derived suppressor cells that exhibited robust inhibition of T-cell growth. We suggest that their influence is likely to explain the host's failure to contain EBV-positive T/NK-cell proliferation.