Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya-ku, Saitama, Saitama, 330-8503, Japan.
J Clin Immunol. 2012 Dec;32(6):1340-52. doi: 10.1007/s10875-012-9729-5. Epub 2012 Jul 5.
Adult T cell leukemia/lymphoma (ATL) is a highly aggressive malignancy of T cells caused by human T cell lymphotropic virus type 1 (HTLV-1). Recent clinical studies have suggested that allogeneic stem cell transplantation (HSCT) improves the clinical course of ATL by harnessing a graft-versus-ATL effect, and that donor-derived HTLV-1 Tax-specific CD8(+) cytotoxic T cells (CTLs) contribute to the graft-versus-ATL effect after HSCT. However, little is known about the immunological characteristics of Tax-specific CTLs in ATL patients who underwent HSCT.
We serially analyzed frequencies, differentiation, functions and clonal dynamics of Tax-specific CTLs in paired samples of peripheral blood (PB) and bone marrow (BM) from an ATL patient after HSCT at the single-cell level. We used flowcytometric and single-cell T cell receptor (TCR) repertoire analysis methods without culture steps.
Donor-derived Tax-specific CTLs effectively suppressed HTLV-1 replication in both PB and BM at least during chronic graft-versus-host disease after HSCT. Furthermore, Tax-specific CTLs had comparable properties between BM and PB, except for preferential accumulation in BM rather than PB. Tax-specific CTLs persistently existed as less-differentiated CD45RA(-)CCR7(-) effector memory CTLs based on predominant phenotypes of CD27(+), CD28(+/-) and CD57(+/-). Our approach using single-cell TCR repertoire analysis method showed highly restricted oligoclonal responses of Tax-specific CTLs, and TCR BV7- or BV30- expressing two predominant CTL clones persistently existed and maintained strong cytotoxic activities against HTLV-1 in both PB and BM over three years after HSCT.
These findings about Tax-specific CTLs provide insights into future directions for studies on immunotherapy against ATL.
成人 T 细胞白血病/淋巴瘤（ATL）是一种由人类 T 细胞嗜淋巴细胞病毒 1 型（HTLV-1）引起的高度侵袭性 T 细胞恶性肿瘤。最近的临床研究表明，异基因造血干细胞移植（HSCT）通过利用移植物抗白血病效应改善 ATL 的临床病程，并且供体来源的 HTLV-1 Tax 特异性 CD8+细胞毒性 T 细胞（CTL）有助于 HSCT 后移植物抗白血病效应。然而，对于接受 HSCT 的 ATL 患者中 Tax 特异性 CTL 的免疫学特征知之甚少。
我们在 HSCT 后，以单细胞水平，连续分析了一位 ATL 患者外周血（PB）和骨髓（BM）配对样本中 Tax 特异性 CTL 的频率、分化、功能和克隆动力学。我们使用了流式细胞术和单细胞 T 细胞受体（TCR）库分析方法，而无需培养步骤。
在 HSCT 后慢性移植物抗宿主病期间，供体来源的 Tax 特异性 CTL 有效地抑制了 PB 和 BM 中的 HTLV-1 复制。此外，Tax 特异性 CTL 在 BM 和 PB 之间具有相似的特性，除了在 BM 中而不是 PB 中优先积累。Tax 特异性 CTL 持续存在为较少分化的 CD45RA(-)CCR7(-)效应记忆 CTL，基于 CD27(+)、CD28(+/-)和 CD57(+/-)的主要表型。我们使用单细胞 TCR 库分析方法的方法显示 Tax 特异性 CTL 的高度受限寡克隆反应，并且 TCR BV7-或 BV30-表达的两个主要 CTL 克隆持续存在，并在 HSCT 后三年内在 PB 和 BM 中保持对 HTLV-1 的强烈细胞毒性活性。
这些关于 Tax 特异性 CTL 的发现为针对 ATL 的免疫治疗研究提供了新的思路。
