On the pathogenicity of autoantigen-specific T-cell receptors

Amanda R. Burton, Erica Vincent, Paula Y. Arnold, Greig P. Lennon, Matthew Smeltzer, Chin-Shang Li, Kathryn Haskins, John Hutton, Roland M. Tisch, Eli E. Sercarz, Pere Santamaria, Creg J. Workman, Dario A A Vignali

Research output: Contribution to journalArticle

73 Scopus citations

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), 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.

Original languageEnglish (US)
Pages (from-to)1321-1330
Number of pages10
JournalDiabetes
Volume57
Issue number5
DOIs
StatePublished - May 2008

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Burton, A. R., Vincent, E., Arnold, P. Y., Lennon, G. P., Smeltzer, M., Li, C-S., Haskins, K., Hutton, J., Tisch, R. M., Sercarz, E. E., Santamaria, P., Workman, C. J., & Vignali, D. A. A. (2008). On the pathogenicity of autoantigen-specific T-cell receptors. Diabetes, 57(5), 1321-1330. https://doi.org/10.2337/db07-1129