Annels N E, Callan M F, Tan L, Rickinson A B
Cancer Research Campaign Institute for Cancer Studies and Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
J Immunol. 2000 Nov 1;165(9):4831-41. doi: 10.4049/jimmunol.165.9.4831.
Infection with EBV provides a unique opportunity to follow the human CD8(+) T cell response to a persistent, genetically stable agent from the primary phase, as seen in infectious mononucleosis (IM) patients, into long-term memory. This study focuses on the response to an immunodominant HLA-A2.01-restricted epitope, GLCTLVAML, from the EBV-lytic cycle Ag BMLF1. TCR analysis of the highly amplified primary response to this epitope revealed markedly oligoclonal receptor usage among in vitro-derived clones, with similar clonotypes dominant in all three IM patients studied. Direct staining of IM T cell preparations with the A2.01/GLCTLVAML tetramer linked this oligoclonal epitope-specific response with appropriate Vbeta subset expansions in the patients' blood. These patients were studied again >2 years later, at which time TCR analysis of in vitro-reactivated clones suggested that rare clonotypes within the primary response had now come to dominate memory. Five additional A2. 01-positive IM patients were studied prospectively for Vbeta subset representation within primary and memory epitope-specific populations as identified by tetramer staining. In each case, the primary response contained large Vbeta2, Vbeta16, or Vbeta22 components, and in three of five cases the originally dominant Vbeta was represented very poorly, if at all, in memory. We conclude 1) that an EBV epitope-specific primary response large enough to account for up to 10% CD8(+) T cells in IM blood may nevertheless be dominated by just a few highly expanded clonotypes, and 2) that with persistent viral challenge such dominant T cell clonotypes may be lost and replaced by others in memory.
感染EB病毒为追踪人类CD8(+) T细胞对一种持续存在、基因稳定的病原体的反应提供了独特的机会，这种反应从急性期开始，如传染性单核细胞增多症（IM）患者所见，一直到长期记忆阶段。本研究聚焦于对EB病毒裂解周期抗原BMLF1中一个免疫显性的、HLA - A2.01限制性表位GLCTLVAML的反应。对该表位高度扩增的初次反应进行TCR分析发现，体外培养的克隆中受体使用明显呈寡克隆性，在所有研究的3例IM患者中，相似的克隆型占主导。用A2.01/GLCTLVAML四聚体直接染色IM T细胞制剂，将这种寡克隆性表位特异性反应与患者血液中适当的Vβ亚群扩增联系起来。在2年多后再次研究这些患者，此时对体外再激活克隆的TCR分析表明，初次反应中罕见的克隆型现已在记忆中占主导。另外对5例A2.01阳性的IM患者进行前瞻性研究，通过四聚体染色确定初次和记忆阶段表位特异性群体中的Vβ亚群表现。在每种情况下，初次反应都包含大量的Vβ2、Vβ16或Vβ22成分，在5例中的3例中，最初占主导的Vβ在记忆中即便有也表现得非常少。我们得出结论：1）在IM血液中，足以占到10% CD8(+) T细胞的EB病毒表位特异性初次反应可能仅由少数高度扩增的克隆型主导；2）在持续的病毒攻击下，这种占主导的T细胞克隆型在记忆中可能会丢失并被其他克隆型取代。
