title: Directed differentiation of induced pluripotent stem cells towards T lymphocytes.
abstract: Adoptive cell transfer (ACT) of antigen-specific CD8(+)  cytotoxic T lymphocytes (CTLs) is a promising treatment for a variety of  malignancies (1). 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 (2-7).  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 (8-10). 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 (11-13), HSCs have reduced differentiation and proliferative capacities, and HSCs are difficult to expand in in vitro cell culture (14-16).  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.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, USA.
authors.forename: Fengyang
authors.initials: F
authors.lastname: Lei
authors.forename: Rizwanul
authors.initials: R
authors.lastname: Haque
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Xiong
authors.forename: Jianxun
authors.initials: J
authors.lastname: Song
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D018920:Coculture Techniques; D003584:Cytological Techniques / Q000379:methods*; D018984:Epitopes, T-Lymphocyte; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D014161:Transduction, Genetic
chemical_list: D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell