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A Unique T-Cell Receptor Amino Acid Sequence Selected by Human T-Cell Lymphotropic Virus Type 1 Tax301-309-Specific Cytotoxic T Cells in HLA-A24:02-Positive Asymptomatic Carriers and Adult T-Cell Leukemia/Lymphoma Patients
Journal of Virology ( IF 5.4 ) Pub Date : 2017-10-01 , DOI: 10.1128/jvi.00974-17
Yuko Ishihara 1 , Yukie Tanaka 1, 2 , Seiichiro Kobayashi 2 , Koji Kawamura 1 , Hideki Nakasone 1 , Ayumi Gomyo 1 , Jin Hayakawa 1 , Masaharu Tamaki 1 , Yu Akahoshi 1 , Naonori Harada 1 , Machiko Kusuda 1 , Kazuaki Kameda 1 , Tomotaka Ugai 1 , Hidenori Wada 1 , Kana Sakamoto 1 , Miki Sato 1 , Kiriko Terasako-Saito 1 , Misato Kikuchi 1 , Shun-ichi Kimura 1 , Aki Tanihara 1 , Shinichi Kako 1 , Kaoru Uchimaru 3 , Yoshinobu Kanda 1
Affiliation  

We previously reported that the T-cell receptor (TCR) repertoire of human T-cell lymphotropic virus type 1 (HTLV-1) Tax301-309-specific CD8+ cytotoxic T cells (Tax301-309-CTLs) was highly restricted and a particular amino acid sequence motif, the PDR motif, was conserved among HLA-A*24:02-positive (HLA-A*24:02+) adult T-cell leukemia/lymphoma (ATL) patients who had undergone allogeneic hematopoietic cell transplantation (allo-HSCT). Furthermore, we found that donor-derived PDR+ CTLs selectively expanded in ATL long-term HSCT survivors with strong CTL activity against HTLV-1. On the other hand, the TCR repertoires in Tax301-309-CTLs of asymptomatic HTLV-1 carriers (ACs) remain unclear. In this study, we directly identified the DNA sequence of complementarity-determining region 3 (CDR3) of the TCR-β chain of Tax301-309-CTLs at the single-cell level and compared not only the TCR repertoires but also the frequencies and phenotypes of Tax301-309-CTLs between ACs and ATL patients. We did not observe any essential difference in the frequencies of Tax301-309-CTLs between ACs and ATL patients. In the single-cell TCR repertoire analysis of Tax301-309-CTLs, 1,458 Tax301-309-CTLs and 140 clones were identified in this cohort. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-β CDR3, was exclusively observed in all ACs and ATL patients. However, there was no correlation between PDR+ CTL frequencies and HTLV-1 proviral load (PVL). In conclusion, we have identified, for the first time, a unique amino acid sequence, PDR, as a public TCR-CDR3 motif against Tax in HLA-A*24:02+ HTLV-1-infected individuals. Further investigations are warranted to elucidate the role of the PDR+ CTL response in the progression from carrier state to ATL.

IMPORTANCE ATL is an aggressive T-cell malignancy caused by HTLV-1 infection. The HTLV-1 regulatory protein Tax aggressively promotes the proliferation of HTLV-1-infected lymphocytes and is also a major target antigen for CD8+ CTLs. In our previous evaluation of Tax301-309-CTLs, we found that a unique amino acid sequence motif, PDR, in CDR3 of the TCR-β chain of Tax301-309-CTLs was conserved among ATL patients after allo-HSCT. Furthermore, the PDR+ Tax301-309-CTL clones selectively expanded and showed strong cytotoxic activities against HTLV-1. On the other hand, it remains unclear how Tax301-309-CTL repertoire exists in ACs. In this study, we comprehensively compared Tax-specific TCR repertoires at the single-cell level between ACs and ATL patients. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-β CDR3, was conserved in all ACs and ATL patients, regardless of clinical subtype in HTLV-1 infection.



中文翻译:

由人类T细胞淋巴病毒1型税301-309选择的独特T细胞受体氨基酸序列-HLA-A24:02阳性的特定细胞毒性T细胞-无症状载体和成人T细胞白血病/淋巴瘤患者

我们以前报道的是,T细胞受体(TCR)的人T细胞亲淋巴病毒1型的曲目(HTLV-1)税收301-309特异性CD8 +细胞毒性T细胞(含税301-309 -CTLs)中的高度限制和在经历了同种异体造血细胞的HLA-A * 24:02阳性(HLA-A * 24:02 +)成人T细胞白血病/淋巴瘤(ATL)患者中,一个特定的氨基酸序列基序PDR基序是保守的移植(allo-HSCT)。此外,我们发现供体来源的PDR + CTL在ATL长期HSCT幸存者中选择性扩展,而AHT长期HSCT存活者对HTLV-1具有强大的CTL活性。另一方面,TCR清单在301-309号税中-无症状HTLV-1携带者(AC)的CTL尚不清楚。在这项研究中,我们直接识别的税的TCR-β链的互补性决定区3(CDR3)的DNA序列301-309在单细胞水平-CTLs相比不仅TCR全集而且频率和税收的表型301-309的AC和ATL患者之间-CTLs。我们并没有观察到税收的频率的任何本质上的区别301-309的AC和ATL患者之间-CTLs。在税收的单细胞T细胞受体库分析301-309 -CTLs,1458个税301-309 -CTLs和140个克隆在这个队列进行鉴定。税金301-309-CTLs显示出严格限制的TCR库,并严重偏爱BV7,并且仅在所有AC和ATL患者中观察到PDR(TCR-βCDR3中的独特基序)。但是,PDR + CTL频率与HTLV-1前病毒载量(PVL)之间没有相关性。总之,我们首次确定了独特的氨基酸序列PDR,作为HLA-A * 24:02 + HTLV-1感染个体中针对Tax的公共TCR-CDR3基序。有必要进行进一步的研究,以阐明PDR + CTL反应在从载体状态到ATL的过程中的作用。

重要信息ATL是由HTLV-1感染引起的侵袭性T细胞恶性肿瘤。HTLV-1调节蛋白Tax积极促进HTLV-1感染的淋巴细胞的增殖,并且也是CD8 + CTL的主要靶抗原。在我们以前的税评估301-309 -CTLs,我们发现一种独特的氨基酸序列基序,PDR,在税收的TCR-β链的CDR3 301-309 -CTLs是ATL患者中保守的异基因造血干细胞移植后。此外,PDR +301-309 -CTL克隆选择性地膨胀并显示对HTLV-1强细胞毒活性。另一方面,目前尚不清楚301-309如何征税AC中存在-CTL曲目。在这项研究中,我们全面比较了AC和ATL患者之间单细胞水平的Tax-specific TCR组成。税务301-309 -CTLs表现出高度限制的TCR剧目与BV7一种强烈的偏见使用,并PDR,在TCR-βCDR3,在所有AC和ATL患者保守,无论临床亚型的独特主题的HTLV-1感染。

更新日期:2017-09-13
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