MHC II tetramers visualize human CD4+ T cell responses to Epstein-Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response
MHC II tetramers visualize human CD4+ T cell responses to Epstein-Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response
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DOI：
10.1084/jem.20121437
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发表时间：
2013-05-06
影响因子：
15.3
通讯作者：
Rickinson, Alan B.
中科院分区：
文献类型：
--
作者：
Long, Heather M.;Chagoury, Odette L.;Rickinson, Alan B.
病毒特异性的CD4(+)T细胞是宿主对病毒感染反应的关键协调者，但与CD8(+)T细胞相比，在单细胞水平上仍然缺乏特征。在这里，我们使用9个MHC II表位多肽四聚体来可视化人类CD4(+)T细胞对EB病毒(EBV)的反应，EBV是传染性单核细胞增多症(IM)的病原体，这种疾病与大量病毒特异性CD8(+)T细胞反应有关。我们发现，虽然没有达到病毒特异性CD8(+)T细胞的扩增幅度，但在急性IM血液中检测到针对潜伏抗原EBNA2和四个裂解周期抗原表位的激活的CD4(+)T细胞的频率很高。然后，它们迅速下降到终生病毒携带者的典型数值，其中大多数四聚体阳性细胞显示传统的记忆标记，但一些出人意料地恢复到幼稚的表型。相反，在IM患者中，CD4(+)T细胞对EBNA1表位的反应大大延迟，这与众所周知但迄今无法解释的EBNA1抗体反应延迟是一致的。我们提出了来自体外系统的证据，可以解释这些不寻常的动力学。与其他EBNAs和裂解周期蛋白不同，EBNA1不是从EBV感染的细胞中自然释放出来的，作为CD4(+)T细胞启动的抗原来源。
Virus-specific CD4(+) T cells are key orchestrators of host responses to viral infection yet, compared with their CD8(+) T cell counterparts, remain poorly characterized at the single cell level. Here we use nine MHC II-epitope peptide tetramers to visualize human CD4(+) T cell responses to Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis (IM), a disease associated with large virus-specific CD8(+) T cell responses. We find that, while not approaching virus-specific CD8(+) T cell expansions in magnitude, activated CD4(+) T cells specific for epitopes in the latent antigen EBNA2 and four lytic cycle antigens are detected at high frequencies in acute IM blood. They then fall rapidly to values typical of life-long virus carriage where most tetramer-positive cells display conventional memory markers but some, unexpectedly, revert to a naive-like phenotype. In contrast CD4(+) T cell responses to EBNA1 epitopes are greatly delayed in IM patients, in line with the well-known but hitherto unexplained delay in EBNA1 IgG antibody responses. We present evidence from an in vitro system that may explain these unusual kinetics. Unlike other EBNAs and lytic cycle proteins, EBNA1 is not naturally released from EBV-infected cells as a source of antigen for CD4(+) T cell priming.