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 as relatively few have been assessed in vivo.

Research Design and Methods: We generated mice possessing a monoclonal population of T cells expressing one of 17 T cell receptors (TCR) specific for either known autoantigens (GAD65, 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 mice (Rg)]. 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 1000 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 TCR can mediate islet infiltration and β cell destruction on their own, and that autoreactivity does not necessarily imply pathogenicity.