title: Generation of β cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice.
abstract: Several β cell antigens recognized by T cells in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D) are also T cell targets in the human disease. While numerous antigen-specific therapies prevent diabetes in NOD mice, successful translation of rodent findings to patients has been difficult. A human leucocyte antigen (HLA)-transgenic mouse model incorporating human β cell-specific T cells might provide a better platform for evaluating antigen-specific therapies. The ability to study such T cells is limited by their low frequency in peripheral blood and the difficulty in obtaining islet-infiltrating T cells from patients. We have worked to overcome this limitation by using lentiviral transduction to 'reprogram' primary human CD8 T cells to express three T cell receptors (TCRs) specific for a peptide derived from the β cell antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP265-273 ) and recognized in the context of the human class I major histocompatibility complex (MHC) molecule HLA-A2. The TCRs bound peptide/MHC multimers with a range of avidities, but all bound with at least 10-fold lower avidity than the anti-viral TCR used for comparison. One exhibited antigenic recognition promiscuity. The β cell-specific human CD8 T cells generated by lentiviral transduction with one of the TCRs released interferon (IFN)-γ in response to antigen and exhibited cytotoxic activity against peptide-pulsed target cells. The cells engrafted in HLA-A2-transgenic NOD-scid IL2rγ(null) mice and could be detected in the blood, spleen and pancreas up to 5 weeks post-transfer, suggesting the utility of this approach for the evaluation of T cell-modulatory therapies for T1D and other T cell-mediated autoimmune diseases.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Babad
authors.forename: G
authors.initials: G
authors.lastname: Mukherjee
authors.forename: A
authors.initials: A
authors.lastname: Follenzi
authors.forename: R
authors.initials: R
authors.lastname: Ali
authors.forename: B O
authors.initials: BO
authors.lastname: Roep
authors.forename: L D
authors.initials: LD
authors.lastname: Shultz
authors.forename: P
authors.initials: P
authors.lastname: Santamaria
authors.forename: O O
authors.initials: OO
authors.lastname: Yang
authors.forename: H
authors.initials: H
authors.lastname: Goldstein
authors.forename: D L
authors.initials: DL
authors.lastname: Greiner
authors.forename: T P
authors.initials: TP
authors.lastname: DiLorenzo
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002470:Cell Survival; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005822:Genetic Vectors / Q000235:genetics*; D005952:Glucose-6-Phosphatase / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D050417:Insulin-Secreting Cells / Q000276:immunology*; D019169:Jurkat Cells; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation
chemical_list: D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human
keywords: CD8 T cells; autoimmunity; type 1 diabetes