Directed differentiation of induced pluripotent stem cells towards T lymphocytes.
Directed differentiation of induced pluripotent stem cells towards T lymphocytes.
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DOI：
10.3791/3986
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发表时间：
2012-05-14
期刊：
影响因子：
--
通讯作者：
Song J
中科院分区：
文献类型：
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作者：
Lei F;Haque R;Xiong X;Song J
从诱导多能干细胞（iPS）产生T淋巴细胞提供了使用胚胎干细胞进行基于T细胞的免疫治疗的替代方法。该方法表明，通过利用体外或体内诱导系统，iPS细胞能够分化为常规和抗原特异性T淋巴细胞。抗原特异性CD8+细胞毒性T淋巴细胞（CTL）的连续细胞转移（ACT）是一种有前途的治疗各种恶性肿瘤的方法。CTL可通过与肿瘤抗原和T细胞受体（TCR）相互作用识别恶性细胞，并释放细胞毒素和细胞因子以杀死恶性细胞。众所周知，分化程度较低和中央记忆样（称为高反应性）的CTL是基于ACT的免疫疗法的最佳群体，因为这些CTL具有高增殖潜力，与分化程度较高的细胞相比更不易于凋亡，并且具有更高的响应稳态细胞因子的能力。然而，由于难以从患者获得大量的此类CTL，因此迫切需要找到一种新的方法来产生用于成功的基于ACT的疗法的高反应性Ag特异性CTL。TCR转导的自我更新的干细胞的免疫重建具有治疗疾病的治疗潜力。然而，从患者身上获得胚胎干细胞（ESC）的方法是不可行的。尽管造血干细胞（hematopoietic stem cells，HSCs）在临床上已被广泛应用于治疗目的，但HSCs的分化和增殖能力较低，且难以在体外细胞培养中扩增。最近的iPS细胞技术和用于基因递送的体外系统的开发能够在没有任何手术方法的情况下从患者产生iPS细胞。此外，与ESC一样，iPS细胞在体外具有无限增殖能力，并已显示可分化为造血细胞。因此，与ESC或HSC相比，iPS细胞具有更大的潜力用于基于ACT的免疫治疗。在这里，我们提出了体外从iPS细胞产生T淋巴细胞的方法，以及体内从iPS细胞编程抗原特异性CTL以促进癌症免疫监视的方法。Notch配体的体外刺激驱动iPS细胞的T细胞分化，TCR基因转导导致iPS细胞在体内分化为抗原特异性T细胞，这阻止了肿瘤生长。因此，我们证明了来自iPS细胞的抗原特异性T细胞分化。我们的研究提供了一种潜在的更有效的方法，为基于ACT的治疗产生抗原特异性CTL，并促进疾病的治疗策略的发展。
Generation of T lymphocytes from induced pluripotent stem (iPS) cells gives an alternative approach of using embryonic stem cells for T cell-based immunotherapy. The method shows that by utilizing either in vitro or in vivo induction system, iPS cells are able to differentiate into both conventional and antigen-specific T lymphocytes. Adoptive cell transfer (ACT) of antigen-specific CD8+ cytotoxic T lymphocytes (CTLs) is a promising treatment for a variety of malignancies . CTLs can recognize malignant cells by interacting tumor antigens with the T cell receptors (TCR), and release cytotoxins as well as cytokines to kill malignant cells. It is known that less-differentiated and central-memory-like (termed highly reactive) CTLs are the optimal population for ACT-based immunotherapy, because these CTLs have a high proliferative potential, are less prone to apoptosis than more differentiated cells and have a higher ability to respond to homeostatic cytokines . However, due to difficulties in obtaining a high number of such CTLs from patients, there is an urgent need to find a new approach to generate highly reactive Ag-specific CTLs for successful ACT-based therapies. TCR transduction of the self-renewable stem cells for immune reconstitution has a therapeutic potential for the treatment of diseases . However, the approach to obtain embryonic stem cells (ESCs) from patients is not feasible. Although the use of hematopoietic stem cells (HSCs) for therapeutic purposes has been widely applied in clinic , HSCs have reduced differentiation and proliferative capacities, and HSCs are difficult to expand in in vitro cell culture . Recent iPS cell technology and the development of an in vitro system for gene delivery are capable of generating iPS cells from patients without any surgical approach. In addition, like ESCs, iPS cells possess indefinite proliferative capacity in vitro, and have been shown to differentiate into hematopoietic cells. Thus, iPS cells have greater potential to be used in ACT-based immunotherapy compared to ESCs or HSCs. Here, we present methods for the generation of T lymphocytes from iPS cells in vitro, and in vivo programming of antigen-specific CTLs from iPS cells for promoting cancer immune surveillance. Stimulation in vitro with a Notch ligand drives T cell differentiation from iPS cells, and TCR gene transduction results in iPS cells differentiating into antigen-specific T cells in vivo, which prevents tumor growth. Thus, we demonstrate antigen-specific T cell differentiation from iPS cells. Our studies provide a potentially more efficient approach for generating antigen-specific CTLs for ACT-based therapies and facilitate the development of therapeutic strategies for diseases.
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影响因子：
7
作者：
Brenner MK;Heslop HE
通讯作者：
Heslop HE
影响因子：
20.3
作者：
Hinrichs, Christian S.;Borman, Zachary A.;Restifo, Nicholas P.
通讯作者：
Restifo, Nicholas P.
影响因子：
32.4
作者：
Stemberger, Christian;Huster, Katharina M.;Busch, Dirk H.
通讯作者：
Busch, Dirk H.
影响因子：
20.3
作者：
Alajez, NM;Schmielau, J;Finn, OJ
通讯作者：
Finn, OJ
影响因子：
82.9
作者：
通讯作者：
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