RNA sequencing identifies clonal structure of T-cell repertoires in patients with adult T-cell leukemia/lymphoma
RNA sequencing identifies clonal structure of T-cell repertoires in patients with adult T-cell leukemia/lymphoma
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DOI：
10.1038/s41525-019-0084-9
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发表时间：
2019-05-06
影响因子：
5.3
通讯作者：
Firouzi, Sanaz
中科院分区：
文献类型：
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作者：
Farmanbar, Amir;Kneller, Robert;Firouzi, Sanaz
由体细胞DNA重排产生的T细胞受体（TCR）库的多样性对于免疫系统功能至关重要。高通量测序技术现在允许在单核苷酸和最近的单细胞分辨率下检查抗原受体库。TCR库可以在感染、恶性肿瘤或免疫病症的情况下改变。在这里，我们研究了TCR克隆性的多样性及其与成人T细胞白血病/淋巴瘤（ATL）的发病机制和预后的关系，ATL是一种由人类T细胞白血病病毒1型（HTLV-1）感染引起的恶性肿瘤。我们分析了来自59例HTLV-1感染者（无症状携带者（AC）、阴燃型、慢性、急性和淋巴瘤ATL亚型）和3例未感染对照的62组高通量RNA测序数据，以评估TCR分布。基于这些TCR谱，CD 4阳性细胞和AC显示多克隆模式，而ATL患者显示寡聚或单克隆模式（样品中平均有446个克隆型）。显性克隆中TCR α和TCR β基因的表达在样本中不同。与慢性、急性和淋巴瘤亚型相比，AC、CD 4阳性样本和阴燃患者显示出显著更高的TCR多样性。ATL患者的CDR 3序列长度分布、氨基酸保守性和基因使用变异性与来自AC和健康供体的外周血细胞相似。因此，通过RNA测序确定单克隆结构和克隆多样性可能有助于预后目的和个性化ATL诊断和治疗评估。
The diversity of T-cell receptor (TCR) repertoires, as generated by somatic DNA rearrangements, is central to immune system function. High-throughput sequencing technologies now allow examination of antigen receptor repertoires at single-nucleotide and, more recently, single-cell resolution. The TCR repertoire can be altered in the context of infections, malignancies or immunological disorders. Here we examined the diversity of TCR clonality and its association with pathogenesis and prognosis in adult T-cell leukemia/lymphoma (ATL), a malignancy caused by infection with human T-cell leukemia virus type-1 (HTLV-1). We analyzed 62 sets of high-throughput RNA sequencing data from 59 samples of HTLV-1-infected individuals-asymptomatic carriers (ACs), smoldering, chronic, acute and lymphoma ATL subtypes-and three uninfected controls to evaluate TCR distribution. Based on these TCR profiles, CD4-positive cells and ACs showed polyclonal patterns, whereas ATL patients showed oligo- or monoclonal patterns (with 446 average clonotypes across samples). Expression of TCR alpha and TCR beta genes in the dominant clone differed among the samples. ACs, CD4-positive samples and smoldering patients showed significantly higher TCR diversity compared with chronic, acute and lymphoma subtypes. CDR3 sequence length distribution, amino acid conservation and gene usage variability for ATL patients resembled those of peripheral blood cells from ACs and healthy donors. Thus, determining monoclonal architecture and clonal diversity by RNA sequencing might be useful for prognostic purposes and for personalizing ATL diagnosis and assessment of treatments.