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Human Dendritic Cell–Derived Induced Pluripotent Stem Cell Lines Are Not Immunogenic Human Dendritic Cell−Derived Induced Pluripotent Stem Cell Lines Are Not Immunogenic This information is current as Arvind Chhabra, I-Ping Chen and Deepika Batra of September 29, 2021. J Immunol 2017; 198:1875-1886; Prepublished online 23 January 2017; doi: 10.4049/jimmunol.1601676 http://www.jimmunol.org/content/198/5/1875 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/01/20/jimmunol.160167 Material 6.DCSupplemental References This article cites 41 articles, 12 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/198/5/1875.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 29, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human Dendritic Cell–Derived Induced Pluripotent Stem Cell Lines Are Not Immunogenic Arvind Chhabra,* I-Ping Chen,† and Deepika Batra* Donor-specific induced pluripotent stem cells (iPSC) can be used to generate desired cell types, including naive immune effectors, for the treatment of different diseases. However, a greater understanding of the inherent immunogenicity of human iPSC and their cellular derivatives is needed for the development of safe and effective cell-replacement therapies, given that studies in mouse mod- els claimed that the syngenic mouse iPSC lines can be immunogenic. We report the characterization of the innate and adaptive immune mechanisms in human iPSC lines derived from peripheral blood–derived dendritic cells using a nonintegrating RNAvirus, Sendai virus. We show that these iPSC lines express mRNA of TLR molecules and the Ag-presentation pathway intermediates; however, these mRNA are not translated into functional proteins, and these iPSC lines do not induce TLR-mediated inflammatory cytokine responses or inflammasome activation. We also show that these iPSC lines do not activate T cells in an allogenic MLR; Downloaded from however, they express low levels of MHC class I molecules that can efficiently acquire antigenic peptides from their microenvi- ronment and present them to Ag-specific T cells. In addition, we show that these iPSC lines can be efficiently differentiated into hematopoietic stem cell precursors, as well as APC, under appropriate culture conditions. Taken together, our data show that the dedifferentiation of human dendritic cells effectively shuts down their immunogenic pathways and implicates transcriptional and posttranscriptional mechanisms in this process. The Journal of Immunology, 2017, 198: 1875–1886. http://www.jimmunol.org/ uman pluripotent stem cells (hPSC) are defined by their MART-127–35 as a model human tumor Ag (4–8). Donor-derived ability to self-renew and to differentiate into different immunogenic dendritic cells (DC) and engineered anti-tumor H cell lineages under appropriate culture conditions. Der- T cells produced encouraging clinical results in active specific ivation of human embryonic stem cell (hESC) lines from early- immunization and T cell adoptive-transfer–based cancer immuno- stage embryos opened up possibilities for the development of therapy settings (9–12); however, the efficacy of these approaches pluripotent stem cell–based cell-replacement therapies (CRT) requires significant improvement. In this context, donor-derived (1), and successful reprogramming of somatic cells into induced iPSC can be a valuable resource for generating autologous naive pluripotent stem cells (iPSC) (2, 3) addressed the ethical issues immune effectors; however, efficient models are needed to system- associated with the therapeutic use of hESC. We are working atically characterize the immunogenicity profiles of human iPSC by guest on September 29, 2021 on developing T cell–based cancer immunotherapy approaches lines and their differentiation potential. utilizing the human melanoma–associated antigenic epitope The need for a systematic analysis of the inherent immunoge- nicity of human iPSC lines was highlighted by recent studies in mouse models that used rejection of iPSC line–induced teratoma *Department of Medicine, School of Medicine, University of Connecticut Health in immune-competent mice as a model to examine the inherent † Center, Farmington, CT 06030; and Department of Oral Health and Diagnostic immunogenicity of iPSC lines. These studies claimed that the Sciences, School of Dental Medicine, University of Connecticut Health Center, Farmington, CT 06030 syngenic mouse iPSC lines, especially those derived with genome- ORCID: 0000-0002-7349-3091 (I-P.C.). integrating viral vectors, are immunogenic (13) and that the inher- ent immunogenicity of these syngenic mouse iPSC lines correlates Received for publication September 28, 2016. Accepted for publication December 30, 2016. with their Ag profiles (14). Although other groups reported min- This work was supported by Stem Cell Seed Grant 10-SCA-23 and Stem Cell Estab- imal or no immunogenicity of mouse syngenic iPSC lines and lished Investigator Grant 13-SCB-05 (both to A.C.) from the State of Connecticut, as their cellular derivatives (15–17), these reports highlighted the well as by Grant 1RR06192 from the National Institutes of Health to the Clinical need for an in-depth characterization of the inherent immunoge- Research Center, University of Connecticut Health Center. nicity of hPSC. hESC lines express low levels of MHC class I A.C. designed the study, conducted the experiments, and wrote the manuscript; D.B. conducted T cell–generation experiments and assisted A.C. in the execution of other molecules (18), exhibit immune-privileged properties (19, 20), experiments; and I-P.C. performed teratoma-generation experiments. and are rejected in immune-competent mice through a T cell– Address correspondence and reprint requests to Dr. Arvind Chhabra, Department of mediated allograft-rejection process (19, 21, 22); however, the Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farm- inherent immunogenicity of human iPSC lines has not been ex- ington, CT 06030. E-mail address: [email protected] amined carefully. In this article, we show that the terminally The online version of this article contains supplemental material. differentiated gold standard for human immunogenic cells, DC, Abbreviations used in this article: 5-Aza, 5-azacytidine; CRT, cell-replacement ther- can be successfully dedifferentiated into the iPSC state using apy; DC, dendritic cell; EB, embryoid body; Flu, influenza-associated MP58–66; hESC, human embryonic stem cell; hPSC, human pluripotent stem cell; hPSC- Sendai virus, a nonintegrating RNA virus. We used these iPSC APC, hPSC-derived APC; HSC, hematopoietic stem cell; iDC, immature DC; iPSC, lines to characterize the status of innate and adaptive immune induced pluripotent stem cell; iPSC-APC, iPSC-derived donor-specific APC; M1, mechanisms that are functional in human peripheral blood– human melanoma–associated MART-127–35; M3, MAGE-3271–279;mDC,matureDC; MEF, mouse embryonic fibroblast; SCF, stem cell factor; TCReng, TCR-engineered; derived DC and show that these iPSC lines are inherently non- TSA, trichostatin A; UCHC, University of Connecticut Health Center; UConn, Uni- immunogenic. We also show that these iPSC lines express low levels versity of Connecticut. of MHC class I molecules, and they can efficiently present antigenic Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 peptides, acquired from their microenvironment, to corresponding www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601676 1876 DEDIFFERENTIATION AND REDIFFERENTIATION OF HUMAN DC Ag-specific T cells; as a result, they are also killed by the CTL. In the indicated Ab, and surface phenotype was analyzed using a FACSCalibur addition, we show that these iPSC lines exhibit potent differentia- (BD Biosciences). Ab against the pluripotency markers Oct-4, Sox-2, tion potential, as reflected by their ability to generate embryoid Nanog, Tra 1-61, and Tra 1-81 for immunofluorescence staining were purchased from Abcam. Intracellular staining was performed using Cytofix/ bodies (EB) that can produce hematopoietic stem cell (HSC) pre- Cytoperm (BD Biosciences). cursors and can be further differentiated into functional APC. Our findings provide a plausible explanation for the rejection of trans- RT-PCR analysis planted syngenic iPSC lines in animal models and demonstrate that RT-PCR was performed to confirm removal of Sendai virus vectors from the DC-derived iPSC lines is an ideal system to characterize the im- iPSC lines generated and pluripotency of the hPSC lines, as well as to munogenicity profile of human iPSC lines. Furthermore, we believe characterize hPSC line–derived EB. In brief, hPSC cultures or hPSC- that the dedifferentiation and redifferentiation model of human DC derived EB were washed with
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