BCR-ABL-specific CD4+ T-helper cells promote the priming of antigen-specific cytotoxic T cells via dendritic cells
BCR-ABL-specific CD4+ T-helper cells promote the priming of antigen-specific cytotoxic T cells via dendritic cells
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DOI：
10.1038/cmi.2016.7
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发表时间：
2018-01-01
影响因子：
24.1
通讯作者：
Uemura, Yasushi
中科院分区：
文献类型：
--
作者：
Ueda, Norihiro;Zhang, Rong;Uemura, Yasushi
酪氨酸激酶抑制剂（TKI）疗法的出现显着改善了慢性粒细胞白血病（CML）慢性期患者的预后。然而，晚期 CML 患者的预后不良以及对 TKI 的终生依赖仍然是挑战；因此，一直在寻找有效的治疗方法。 BCR-ABL p210 融合蛋白的连接区域代表白血病特异性新抗原，因此是抗原特异性 T 细胞免疫治疗的一个有吸引力的靶点。 BCR-ABL p210融合区特异性CD4+T辅助性(Th)细胞具有抗白血病潜力，但其功能仍不清楚。在本研究中，我们建立了 BCR-ABL p210 b3a2 融合区特异性 CD4(+) Th 细胞克隆（b3a2 特异性 Th 克隆），并检测了其树突状细胞 (DC) 介导的抗白血病潜力。 b3a2 特异性 Th 克隆识别 HLA-DRB1*09:01 背景下的 b3a2 肽，并表现出 Th1 谱。通过 T 细胞抗原受体刺激激活该克隆触发了 DC 成熟，DC 上调 CD86 和 IL-12p70 的产生表明了这一点，这取决于 b3a2 特异性 Th 细胞上表达的 CD40L 与 CD40 的连接。此外，在 HLA-A*24:02 限制性肾母细胞瘤 1 (WT1)(235-243) 肽存在的情况下，b3a2 特异性 Th 细胞条件化的 DC 有效刺激了 WTI 特异性细胞毒性 T 淋巴细胞 (CTL) 的初次扩增。扩增的 CTL 对负载 WT1(235-243) 肽的 HLA-A*24:02 阳性细胞系具有细胞毒性，并在体内发挥有效的抗白血病作用。然而，b3a2 特异性 Th 克隆介导的抗白血病 CTL 反应受到 TKI 和干扰素-a 的强烈抑制。我们的研究结果表明 b3a2 特异性 Th 细胞在白血病抗原特异性 CTL 介导的免疫中发挥着至关重要的作用，并为建立新型 CML 免疫疗法提供了实验基础。
The advent of tyrosine kinase inhibitor (TKI) therapy markedly improved the outcome of patients with chronic-phase chronic myeloid leukemia (CML). However, the poor prognosis of patients with advanced-phase CML and the lifelong dependency on TKIs are remaining challenges; therefore, an effective therapeutic has been sought. The BCR-ABL p210 fusion protein's junction region represents a leukemia-specific neoantigen and is thus an attractive target for antigen-specific T-cell immunotherapy. BCR-ABL p210 fusion-region-specific CD4(+) T-helper (Th) cells possess antileukemic potential, but their function remains unclear. In this study, we established a BCR-ABL p210 b3a2 fusion-region-specific CD4(+) Th-cell clone (b3a2-specific Th clone) and examined its dendritic cell (DC)-mediated antileukemic potential. The b3a2-specific Th clone recognized the b3a2 peptide in the context of HLA-DRB1*09: 01 and exhibited a Th1profile. Activation of this clone through T-cell antigen receptor stimulation triggered DC maturation, as indicated by upregulated production of CD86 and IL-12p70 by DCs, which depended on CD40 ligation by CD40L expressed on b3a2-specific Th cells. Moreover, in the presence of HLA-A*24:02-restricted Wilms tumor 1 (WT1)(235-243) peptide, DCs conditioned by b3a2-specific Th cells efficiently stimulated the primary expansion of WTI-specific cytotoxic T lymphocytes (CTLs). The expanded CTLs were cytotoxic toward WT1(235-243)-peptide-loaded HLA-A*24:02-positive cell lines and exerted a potent antileukemic effect in vivo. However, the b3a2-specific Th-clone-mediated antileukemic CTL responses were strongly inhibited by both TKIs and interferon-a. Our findings indicate a crucial role of b3a2-specific Th cells in leukemia antigen-specific CTL-mediated immunity and provide an experimental basis for establishing novel CML immunotherapies.