title: Toxin-coupled MHC class I tetramers can specifically ablate autoreactive CD8+ T cells and delay diabetes in nonobese diabetic mice.
abstract: There is compelling evidence that self-reactive CD8(+) T cells are a major factor in development and progression of type 1 diabetes in animals and humans. Hence, great effort has been expended to define the specificity of autoimmune CD8(+) T cells and to alter their responses. Much work has focused on tolerization of T cells using proteins or peptides. A weakness in this approach is that residual autoreactive T cells may be activated and exacerbate disease. In this report, we use a novel approach, toxin-coupled MHC class I tetramers. Used for some time to identify Ag-specific cells, in this study, we use that same property to delete the Ag-specific cells. We show that saporin-coupled tetramers can delete islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive T cells in vitro and in vivo. Sequence analysis of TCRbeta-chains of IGRP(+) cells reveals the repertoire complexity in the islets is markedly decreased as NOD mice age and significantly altered in toxic tetramer-treated NOD mice. Further tetramer(+) T cells in the islets are almost completely deleted, and, surprisingly, loss of tetramer(+) T cells in the islets is long lasting. Finally, we show deletion at 8 wk of age of IGRP(+) CD8(+) T cells, but not dystophia myotonica kinase- or insulin B-reactive cells, significantly delays diabetes in NOD mice.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Vincent
authors.forename: Ellen F
authors.initials: EF
authors.lastname: Young
authors.forename: Adam S
authors.initials: AS
authors.lastname: Buntzman
authors.forename: Rosemary
authors.initials: R
authors.lastname: Stevens
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kepler
authors.forename: Roland M
authors.initials: RM
authors.lastname: Tisch
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Frelinger
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hess
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005952:Glucose-6-Phosphatase / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology; D006183:H-2 Antigens / Q000008:administration & dosage* / Q000633:toxicity; D064532:Histocompatibility Antigen H-2D; D000922:Immunotoxins / Q000008:administration & dosage* / Q000633:toxicity; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D018716:Molecular Mimicry / Q000276:immunology; D011506:Proteins / Q000008:administration & dosage / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D054789:Ribosome Inactivating Proteins, Type 1 / Q000008:administration & dosage / Q000633:toxicity*; D000076985:Saporins; D001613:beta 2-Microglobulin / Q000008:administration & dosage* / Q000633:toxicity
chemical_list: D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D064532:Histocompatibility Antigen H-2D; D000922:Immunotoxins; D011506:Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054789:Ribosome Inactivating Proteins, Type 1; D001613:beta 2-Microglobulin; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse; D000076985:Saporins