On the pathogenicity of autoantigen-specific T-cell receptors
| Autor: | Matthew P. Smeltzer, Pere Santamaria, Paula Y. Arnold, Dario A. A. Vignali, Amanda R. Burton, Eli E. Sercarz, Kathryn Haskins, Creg J. Workman, John C. Hutton, Erica Vincent, Roland Tisch, Chin-Shang Li, Greig P. Lennon |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Adoptive cell transfer Endocrinology Diabetes and Metabolism T cell T-Lymphocytes Receptors Antigen T-Cell Mice SCID Biology Autoantigens Interleukin 21 Islets of Langerhans Mice Antigen Mice Inbred NOD Insulin-Secreting Cells Internal Medicine medicine Cytotoxic T cell Animals Humans Antigen-presenting cell Crosses Genetic Glutamate Decarboxylase Reverse Transcriptase Polymerase Chain Reaction T-cell receptor medicine.disease Molecular biology Adoptive Transfer medicine.anatomical_structure Diabetes Mellitus Type 1 Immunology Female Insulitis Stem Cell Transplantation |
| Zdroj: | Diabetes. 57(5) |
| ISSN: | 1939-327X |
| Popis: | OBJECTIVE—Type 1 diabetes is mediated by T-cell entry into pancreatic islets and destruction of insulin-producing β-cells. The relative contribution of T-cells specific for different autoantigens is largely unknown because relatively few have been assessed in vivo.RESEARCH DESIGN AND METHODS—We generated mice possessing a monoclonal population of T-cells expressing 1 of 17 T-cell receptors (TCR) specific for either known autoantigens (GAD65, insulinoma-associated protein 2 (IA2), IA2β/phogrin, and insulin), unknown islet antigens, or control antigens on a NOD.scid background using retroviral-mediated stem cell gene transfer and 2A-linked multicistronic retroviral vectors (referred to herein as retrogenic [Rg] mice). The TCR Rg approach provides a mechanism by which T-cells with broad phenotypic differences can be directly compared.RESULTS—Neither GAD- nor IA2-specific TCRs mediated T-cell islet infiltration or diabetes even though T-cells developed in these Rg mice and responded to their cognate epitope. IA2β/phogrin and insulin-specific Rg T-cells produced variable levels of insulitis, with one TCR producing delayed diabetes. Three TCRs specific for unknown islet antigens produced a hierarchy of insulitogenic and diabetogenic potential (BDC-2.5 > NY4.1 > BDC-6.9), while a fourth (BDC-10.1) mediated dramatically accelerated disease, with all mice diabetic by day 33, well before full T-cell reconstitution (days 42–56). Remarkably, as few as 1,000 BDC-10.1 Rg T-cells caused rapid diabetes following adoptive transfer into NOD.scid mice.CONCLUSIONS—Our data show that relatively few autoantigen-specific TCRs can mediate islet infiltration and β-cell destruction on their own and that autoreactivity does not necessarily imply pathogenicity. |
| Databáze: | OpenAIRE |
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