Major TCR Repertoire Perturbation by Immunodominant HLA-B*44:03-Restricted CMV-Specific T Cells
Major TCR Repertoire Perturbation by Immunodominant HLA-B*44:03-Restricted CMV-Specific T Cells
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DOI：
10.3389/fimmu.2018.02539
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发表时间：
2018-11-14
影响因子：
7.3
通讯作者：
Goulder, Philip
中科院分区：
文献类型：
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作者：
Attaf, Meriem;Malik, Amna;Goulder, Philip
慢性人类巨细胞病毒 (CMV) 感染期间无疾病取决于高频 CMV 特异性 T 细胞反应的维持。这种反应背后的 T 细胞受体 (TCR) 组成部分仍不清楚，特别是在巨细胞病毒从婴儿期开始流行的非洲人群中。在这里，我们重点关注受 HLA-B*44:03 限制的立即早期 2 (IE-2) 衍生表位 NEGVKAAW (NW8) 的免疫显性 CD8+ T 细胞反应，这是非洲人群中高度普遍的反应，在某些受试者中代表了循环 CD8+ T 细胞的 10% 以上。通过 pMHC 多聚体染色和 NW8 特异性 T 细胞分选，针对 NW8 产生的 TCR 库在 20 名 HLA-B*44:03 受试者中使用高通量测序进行了表征。我们发现响应 NW8 而产生的 CD8+ T 细胞库高度倾斜，并且优先使用一组有限的 V 和 J 基因片段。此外，正如在针对 CMV 和 Epstein-Barr 病毒 (EBV) 等古代病毒的免疫中经常看到的那样，反应主要由多个个体共享的相同 TCR 序列或“公共”TCR 主导。最后，我们描述了一对“超级主导”TCR 克隆型，它们是种系或接近种系编码的，并且在某些个体中以非常高的频率产生，其中单个 CMV 特异性克隆型占所有 CD8+ T 细胞的 17%。考虑到 NW8 反应的强度，我们认为 CMV 特异性免疫的这种重大偏差会导致 HLA-B*44:03 个体的总体 TCR 库发生巨大扰动。
Lack of disease during chronic human cytomegalovirus (CMV) infection depends on the maintenance of a high-frequency CMV-specific T cell response. The composition of the T cell receptor (TCR) repertoire underlying this response remains poorly characterised, especially within African populations in which CMV is endemic from infancy. Here we focus on the immunodominant CD8+ T cell response to the immediate-early 2 (IE-2)-derived epitope NEGVKAAW (NW8) restricted by HLA-B*44:03, a highly prevalent response in African populations, which in some subjects represents >10% of the circulating CD8+ T cells. Using pMHC multimer staining and sorting of NW8-specific T cells, the TCR repertoire raised against NW8 was characterised here using high-throughput sequencing in 20 HLA-B*44:03 subjects. We found that the CD8+ T cell repertoire raised in response to NW8 was highly skewed and featured preferential use of a restricted set of V and J gene segments. Furthermore, as often seen in immunity against ancient viruses like CMV and Epstein-Barr virus (EBV), the response was strongly dominated by identical TCR sequences shared by multiple individuals, or "public" TCRs. Finally, we describe a pair "superdominant" TCR clonotypes, which were germline or nearly germline-encoded and produced at remarkably high frequencies in certain individuals, with a single CMV-specific clonotype representing up to 17% of all CD8+ T cells. Given the magnitude of the NW8 response, we propose that this major skewing of CMV-specific immunity leads to massive perturbations in the overall TCR repertoire in HLA-B*44:03 individuals.