On the Pathogenicity of Autoantigen-Specific T-Cell Receptors

On the Pathogenicity of Autoantigen-Specific T-Cell Receptors Amanda R. Burton 1 , Erica Vincent 1 , Paula Y. Arnold 1 , Greig P. Lennon 1 , Matthew Smeltzer 2 , Chin-Shang Li 3 , Kathryn Haskins 4 , John Hutton 5 , Roland M. Tisch 6 , Eli E. Sercarz 7 , Pere Santamaria 8 , Creg J. Workman 1 and Dario A.A. Vignali 1 1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 2 Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee 3 Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, Californnia 4 Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado 5 Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, Colorado 6 Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 7 Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, California 8 Julia McFarlane Diabetes Research Centre and the Department of Microbiology and Infectious Diseases, Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada Corresponding author: Dr. Dario Vignali, Department of Immunology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. E-mail: dario.vignali{at}stjude.org Abstract 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 o