title: Generation of human islet-specific regulatory T cells by TCR gene transfer.
abstract: Based on the success in animal models of type 1 diabetes (T1D), clinical trials of adoptive regulatory T cell (Treg) therapy are underway using ex vivo expanded polyclonal Tregs. However, pre-clinical data also demonstrate that islet-specific Tregs are more potent than polyclonal Tregs at reversing T1D. Translation of this approach into man will require methods to generate large populations of islet-specific Tregs which, to date, has proved to be a major hurdle. Here we demonstrate the feasibility of lentiviral-mediated T cell receptor (TCR) gene transfer to confer antigen specificity on polyclonal human Tregs. Targeting has been achieved using TCRs isolated from human islet-specific and viral-specific CD4+T cell clones. Engineered T cells demonstrated expression of ectopically-delivered TCRs, resulting in endowment of cognate antigen-specific responses. This enabled antigen-specific suppression at increased potency compared to polyclonal Tregs. However, cells transduced with islet-specific TCRs were less responsive to cognate antigen than viral-specific TCRs, and in some cases, required additional methods to isolate functional antigen-specific Tregs. This study demonstrates the potential of TCR gene transfer to develop islet-specific Treg therapies for effective treatment of T1D, but also highlights that additional optimisation may be required to achieve its full potential.
authors.affiliation: Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London SE1 9RT, UK; NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London SE1 9RT, UK. Electronic address: caroline.hull@kcl.ac.uk.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Hull
authors.affiliation: Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London SE1 9RT, UK; NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London SE1 9RT, UK.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Nickolay
authors.affiliation: Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London SE1 9RT, UK; NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London SE1 9RT, UK.
authors.forename: Megan
authors.initials: M
authors.lastname: Estorninho
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Max W
authors.initials: MW
authors.lastname: Richardson
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.affiliation: Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London SE1 9RT, UK; Peak Therapeutics, London SE24 9LG, UK; Division of Diabetes and Nutrition, King's College London, SE1 1UL, UK; NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London SE1 9RT, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
authors.affiliation: NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London SE1 9RT, UK; CAR Mechanics Group, Division of Cancer Studies, Guy's Hospital Campus, King's College London School of Medicine, London SE1 1UL, UK; Department of Allergy and Immunology, King's College Hospital National Health Service Foundation Trust, London SE5 9RS, UK.
authors.forename: John
authors.initials: J
authors.lastname: Maher
authors.affiliation: Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London SE1 9RT, UK; NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London SE1 9RT, UK. Electronic address: timothy.tree@kcl.ac.uk.
authors.forename: Timothy I M
authors.initials: TI
authors.lastname: Tree
mesh_terms: D000818:Animals; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D023061:Gene Order; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D019169:Jurkat Cells; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell
keywords: Cell therapy; Diabetes; Regulatory T cells; TCR gene therapy