Kusuda Machiko, Nakasone Hideki, Yoshimura Kazuki, Okada Yosuke, Tamaki Masaharu, Matsuoka Akari, Ishikawa Takuto, Meno Tomohiro, Nakamura Yuhei, Kawamura Masakatsu, Takeshita Junko, Kawamura Shunto, Yoshino Nozomu, Misaki Yukiko, Gomyo Ayumi, Tanihara Aki, Kimura Shun-Ichi, Kako Shinichi, Kanda Yoshinobu
Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan.
Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medicial University, Shimotsuke, Japan.
Br J Haematol. 2023 Aug;202(3):578-588. doi: 10.1111/bjh.18918. Epub 2023 Jun 15.
Adult T-cell leukaemia/lymphoma (ATL) is an aggressive malignancy of peripheral T cells caused by human T-cell lymphotropic virus type-1 (HTLV-1). Tax is the most important regulatory protein for HTLV-1. We aimed to reveal a unique amino acid sequence (AA) of complementarity-determining region 3 (CDR3) of the T-cell receptor (TCR)β and TCRα chains of HLA-A*02:01-restricted Tax -specific cytotoxic T cells (Tax-CTLs). The gene expression profiles (GEP) of Tax-CTLs were assessed by the next-generation sequence (NGS) method with SMARTer technology. Tax-CTLs seemed to be oligoclonal, and their gene compositions were skewed. The unique motifs of 'DSWGK' in TCRα and 'LAG' in TCRβ at CDR3 were observed in almost all patients. Tax-CTL clones harbouring the 'LAG' motif with BV28 had a higher binding score than those without either of them, besides a higher binding score associated with longer survival. Tax-CTLs established from a single cell showed killing activities against Tax-peptide-pulsed HLA-A2 T2 cell lines. GEP of Tax-CTLs revealed that genes associated with immune response activity were well preserved in long-term survivors with stable status. These methods and results can help us better understand immunity against ATL, and should contribute to future studies on the clinical application of adoptive T-cell therapies.
成人T细胞白血病/淋巴瘤（ATL）是由1型人类嗜T细胞病毒（HTLV-1）引起的外周T细胞侵袭性恶性肿瘤。Tax是HTLV-1最重要的调节蛋白。我们旨在揭示HLA-A*02:01限制性Tax特异性细胞毒性T细胞（Tax-CTLs）的T细胞受体（TCR）β和TCRα链互补决定区3（CDR3）的独特氨基酸序列（AA）。采用具有SMARTer技术的下一代测序（NGS）方法评估Tax-CTLs的基因表达谱（GEP）。Tax-CTLs似乎是寡克隆的，其基因组成存在偏倚。在几乎所有患者中，均观察到CDR3处TCRα中的“DSWGK”和TCRβ中的“LAG”独特基序。除了与更长生存期相关的更高结合分数外，含有“LAG”基序和BV28的Tax-CTL克隆的结合分数高于不含有这两者的克隆。从单细胞建立的Tax-CTLs对Tax肽脉冲的HLA-A2 T2细胞系具有杀伤活性。Tax-CTLs的GEP显示，与免疫反应活性相关的基因在状态稳定的长期存活者中保存良好。这些方法和结果有助于我们更好地理解针对ATL的免疫，应为未来过继性T细胞疗法的临床应用研究做出贡献。
