1. On the pathogenicity of autoantigen-specific T-cell receptors
- Author
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Burton, Amanda R., Vincent, Erica, Arnold, Paula Y., Lennon, Greig P., Smeltzer, Matthew, Li, Chin-Shang, Haskins, Kathryn, Hutton, John, Tisch, Roland M., Sercarz, Eli E., Santamaria, Pere, Workman, Creg J., and Vignali, Dario A.A.
- Subjects
T cells -- Receptors ,Antigen receptors, T cell -- Properties -- Health aspects -- Research ,Islands of Langerhans -- Properties -- Health aspects -- Research ,Type 1 diabetes -- Research ,Autoantigens -- Properties -- Health aspects -- Research ,Health ,Research ,Properties ,Health aspects - 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 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., Autoimmune type 1 diabetes is a chronic, complex autoimmune disease mediated by the infiltration of autoreactive lymphocytes into the pancreas, resulting in the destruction of the insulin-producing β-cells in the [...]
- Published
- 2008