Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom.
Front Immunol. 2020 Sep 30;11:1587. doi: 10.3389/fimmu.2020.01587. eCollection 2020.
Human cytomegalovirus (CMV) is a highly prevalent herpesvirus, particularly in sub-Saharan Africa, where it is endemic from infancy. The T cell response against CMV is important in keeping the virus in check, with CD8 T cells playing a major role in the control of CMV viraemia. Human leukocyte antigen (HLA) B44:03-positive individuals raise a robust response against the NEGVKAAW (NW8) epitope, derived from the immediate-early-2 (IE-2) protein. We previously showed that the T cell receptor (TCR) repertoire raised against the NW8-HLA-B44:03 complex was oligoclonal and characterised by superdominant clones, which were shared amongst unrelated individuals (i.e., "public"). Here, we address the question of how stable the CMV-specific TCR repertoire is over the course of infection, and whether substantial differences are evident in TCR repertoires in children, compared with adults. We present a longitudinal study of four HIV/CMV co-infected mother-child pairs, who in each case express HLA-B44:03 and make responses to the NW8 epitope, and analyse their TCR repertoire over a period spanning more than 10 years. Using high-throughput sequencing, the paediatric CMV-specific repertoire was found to be highly diverse. In addition, paediatric repertoires were remarkably similar to adults, with public TCR responses being shared amongst children and adults alike. The CMV-specific repertoire in both adults and children displayed strong fluctuations in TCR clonality and repertoire architecture over time. Previously characterised superdominant clonotypes were readily identifiable in the children at high frequency, suggesting that the distortion of the CMV-specific repertoire is incurred as a direct result of CMV infection rather than a product of age-related "memory inflation." Early distortion of the TCR repertoire was particularly apparent in the case of the TCR-β chain, where oligoclonality was low in children and positively correlated with age, a feature we did not observe for TCR-α. This discrepancy between TCR-α and -β chain repertoire may reflect differential contribution to NW8 recognition. Altogether, the results of the present study provide insight into the formation of the TCR repertoire in early life and pave the way to better understanding of CD8 T cell responses to CMV at the molecular level.
人巨细胞病毒（CMV）是一种高度流行的疱疹病毒，特别是在撒哈拉以南非洲地区，该病毒在婴儿时期就已流行。CMV 的 T 细胞反应对于控制病毒至关重要，其中 CD8 T 细胞在控制 CMV 病毒血症方面发挥主要作用。人类白细胞抗原（HLA）B44:03 阳性个体对来源于即刻早期-2（IE-2）蛋白的 NEGVKAAW（NW8）表位产生强烈的反应。我们之前的研究表明，针对 NW8-HLA-B44:03 复合物的 T 细胞受体（TCR） repertoire 是寡克隆的，其特征是超优势克隆，这些克隆在无亲缘关系的个体中共享（即“公共”）。在这里，我们研究了 CMV 特异性 TCR repertoire 在感染过程中的稳定性问题，以及儿童与成人的 TCR repertoire 是否存在明显差异。我们对四对 HIV/CMV 共感染的母婴进行了纵向研究，他们每个人都表达 HLA-B44:03，并对 NW8 表位产生反应，我们分析了他们的 TCR repertoire 超过 10 年的时间。通过高通量测序，我们发现儿科 CMV 特异性 repertoire 具有高度多样性。此外，儿科 repertoire 与成人非常相似，公共 TCR 反应在儿童和成人中都有共享。无论是成人还是儿童，CMV 特异性 repertoire 随着时间的推移，TCR 克隆性和 repertoire 结构都发生了强烈的波动。之前表征的超优势克隆类型在儿童中高频出现，这表明 CMV 特异性 repertoire 的扭曲是由 CMV 感染直接引起的，而不是年龄相关的“记忆膨胀”的结果。在 TCR repertoire 的早期扭曲中，TCR-β链尤其明显，儿童中寡克隆性较低，且与年龄呈正相关，而我们在 TCR-α 中没有观察到这一特征。TCR-α和-TCR-β链 repertoire 之间的这种差异可能反映了对 NW8 识别的不同贡献。总的来说，本研究的结果提供了对生命早期 TCR repertoire 形成的深入了解，并为更好地理解 CD8 T 细胞对 CMV 的分子水平反应铺平了道路。
