Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells
Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells
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DOI：
10.1182/blood-2011-02-339135
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发表时间：
2011-07-28
期刊：
影响因子：
20.3
通讯作者：
Silva-Santos, Bruno
中科院分区：
文献类型：
--
作者：
Correia, Daniel V.;Fogli, Manuela;Silva-Santos, Bruno
癌症免疫治疗的成功取决于杀伤淋巴细胞对生产性肿瘤细胞的识别。γ δ T细胞是一群先天性的淋巴细胞，具有针对肿瘤细胞的强的、MHC不受限制的细胞毒性。尽管如此，我们最近发现，大部分人血液肿瘤对γ δ外周血淋巴细胞（PBL）具有抗性，所述γ δ外周血淋巴细胞（PBL）用高度流行的V γ 9V δ 2 TCR的特异性激动剂活化。虽然这可能构成了一个重要的限制，目前的γ δ T细胞介导的免疫治疗策略，我们在这里描述的分化的V δ 2（-）V δ 1（+）PBL表达天然细胞毒性受体（NCR），直接介导杀死白血病细胞系和慢性淋巴细胞白血病患者肿瘤细胞的一个新的子集。我们表明，V δ 1（+）T细胞可以选择性诱导表达NKp 30，NKp 44和NKp 46，通过一个过程，需要功能性磷脂酰肌醇3-激酶（PI-3 K）/AKT信号刺激与γ（c）细胞因子和TCR激动剂。NCR的稳定表达与高水平的颗粒酶B和增强的针对淋巴样白血病细胞的细胞毒性相关。特异性功能获得和功能丧失实验表明，NKp 30对TCR非依赖性白血病细胞识别做出了最重要的贡献。因此，NKp 30（+）V delta 1（+）T细胞构成了一种新的、可诱导的和特化的杀伤淋巴细胞群体，具有用于人类癌症免疫治疗的高潜力。（血。2011; 118（4）：992-1001）
The success of cancer immunotherapy depends on productive tumor cell recognition by killer lymphocytes. gamma delta T cells are a population of innate-like lymphocytes endowed with strong, MHC-unrestricted cytotoxicity against tumor cells. This notwithstanding, we recently showed that a large proportion of human hematologic tumors is resistant to gamma delta peripheral blood lymphocytes (PBLs) activated with specific agonists to the highly prevalent V gamma 9V delta 2 TCR. Although this probably constitutes an important limitation to current gamma delta T cell-mediated immunotherapy strategies, we describe here the differentiation of a novel subset of V delta 2(-) V delta 1(+) PBLs expressing natural cytotoxicity receptors (NCRs) that directly mediate killing of leukemia cell lines and chronic lymphocytic leukemia patient neoplastic cells. We show that V delta 1(+) T cells can be selectively induced to express NKp30, NKp44 and NKp46, through a process that requires functional phosphatidylinositol 3-kinase (PI-3K)/AKT signaling on stimulation with gamma(c) cytokines and TCR agonists. The stable expression of NCRs is associated with high levels of granzyme B and enhanced cytotoxicity against lymphoid leukemia cells. Specific gain-of-function and loss-of-function experiments demonstrated that NKp30 makes the most important contribution to TCR-independent leukemia cell recognition. Thus, NKp30(+)V delta 1(+) T cells constitute a novel, inducible and specialized killer lymphocyte population with high potential for immunotherapy of human cancer. (Blood. 2011; 118(4): 992-1001)