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On the Pathogenicity of Autoantigen-Specific T-Cell Receptors

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

Abbreviations: FACS, fluorescence-activated cell sorter; GFP, green fluorescent protein; HBSS, Hank's Balanced Salt Solution; FBS, fetal bovine serum; IA2, insulinoma-associated protein 2; ILN, inguinal lymph node; HEL, Hen egg white lysozyme; PE, phycoerythrin; PLN, pancreatic lymph node; TCR, T-cell receptor

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.

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