title: Nuclear transfer nTreg model reveals fate-determining TCR-β and novel peripheral nTreg precursors.
abstract: To study the development and function of "natural-arising" T regulatory (nTreg) cells, we developed a novel nTreg model on pure nonobese diabetic background using epigenetic reprogramming via somatic cell nuclear transfer. On RAG1-deficient background, we found that monoclonal FoxP3(+)CD4(+)Treg cells developed in the thymus in the absence of other T cells. Adoptive transfer experiments revealed that the thymic niche is not a limiting factor in nTreg development. In addition, we showed that the T-cell receptor (TCR) β-chain of our nTreg model was not only sufficient to bias T-cell development toward the CD4 lineage, but we also demonstrated that this TCR β-chain was able to provide stronger TCR signals. This TCR-β-driven mechanism would thus unify former per se contradicting hypotheses of TCR-dependent and -independent nTreg development. Strikingly, peripheral FoxP3(-)CD4(+)T cells expressing the same TCR as this somatic cell nuclear transfer nTreg model had a reduced capability to differentiate into Th1 cells but were poised to differentiate better into induced nTreg cells, both in vitro and in vivo, representing a novel peripheral precursor subset of nTreg cells to which we refer to as pre-nTreg cells.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Manching
authors.initials: M
authors.lastname: Ku
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Shih-En
authors.initials: SE
authors.lastname: Chang
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Julio
authors.initials: J
authors.lastname: Hernandez
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Abadejos
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Sabouri-Ghomi
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Niklas J
authors.initials: NJ
authors.lastname: Muenchmeier
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Anna
authors.initials: A
authors.lastname: Schwarz
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Valencia
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037 kirak@scripps.edu.
authors.forename: Oktay
authors.initials: O
authors.lastname: Kirak
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D053652:Nuclear Transfer Techniques; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: SCNT; TCR-β; nTreg; pre-nTreg; somatic cell nuclear transfer