title: Stem cell-derived tissue-associated regulatory T cells ameliorate the development of autoimmunity.
abstract: Pluripotent stem cells (PSCs) have the potential to produce almost all of the cells in the body, including regulatory T cells (Tregs). However, the exact conditions required for the development of antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) are not well delineated. Ag-specific PSC-Tregs can be tissue/organ-associated and migrate to local inflamed tissues/organs to suppress the autoimmune response after adoptive transfer, thereby avoiding potential overall immunosuppression from non-specific Tregs. In this study, we developed a new approach to generate functional Ag-specific Tregs from induced PSCs (iPSCs), i.e., iPSC-Tregs, which had the ability to generate an Ag-specific immunosuppressive response in a murine model of arthritis. We retrovirally transduced murine iPSCs with a construct containing genes of Ag-specific T cell receptor (TCR) and the transcriptional factor FoxP3. We differentiated the iPSCs into Ag-specific iPSC-Tregs using in vitro or in vivo Notch signaling, and demonstrated that adoptive transfer of such Tregs dramatically suppressed autoimmunity in a well-established Ag-induced arthritis model, including the inflammation, joint destruction, cartilage prostaglandin depletion, osteoclast activity, and Th17 production. Our results indicate that PSCs can be used to develop Ag-specific Tregs, which have a therapeutic potential for Treg-based therapies of autoimmune disorders.
authors: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors: Mohammad
authors: M
authors: Haque
authors: Institutes of Irradiation/Immunology, The Third Military Medical University, Chongqing 400038, China.
authors: Jianyong
authors: J
authors: Song
authors: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors: Kristin
authors: K
authors: Fino
authors: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors: Praneet
authors: P
authors: Sandhu
authors: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors: Xinmeng
authors: X
authors: Song
authors: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors: Fengyang
authors: F
authors: Lei
authors: Department of Medicine, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors: Songguo
authors: S
authors: Zheng
authors: Institutes of Irradiation/Immunology, The Third Military Medical University, Chongqing 400038, China.
authors: Bing
authors: B
authors: Ni
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Deyu
authors: D
authors: Fang
authors: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors: Jianxun
authors: J
authors: Song
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D015551:Autoimmunity; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D014161:Transduction, Genetic
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011948:Receptors, Antigen, T-Cell