On the pathogenicity of autoantigen-specific T-cell receptors
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), IA27beta;/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. LA2β/ 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 autoanti-gen-specific TCRs can mediate islet infiltration and β-cell destruction on their own and that autoreactivity does not necessarily imply pathogenicity. © 2008 by the American Diabetes Association.
Burton, A., Vincent, E., Arnold, P., Lennon, G., Smeltzer, M., Li, C., Haskins, K., Hutton, J., Tisch, R., Sercarz, E., Santamaria, P., Workman, C., & Vignali, D. (2008). On the pathogenicity of autoantigen-specific T-cell receptors. Diabetes, 57 (5), 1321-1330. https://doi.org/10.2337/db07-1129