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 beta-cells. The relative contribution of T-cells specific for different autoantigens is largely unknown because relatively few have been assessed in vivo.


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), IA2beta/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. IA2beta/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 beta-cell destruction on their own and that autoreactivity does not necessarily imply pathogenicity.
Burton
Amanda R
AR
Department of Immunology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA.
Vincent
Erica
E
Arnold
Paula Y
PY
Lennon
Greig P
GP
Smeltzer
Matthew
M
Li
Chin-Shang
CS
Haskins
Kathryn
K
Hutton
John
J
Tisch
Roland M
RM
Sercarz
Eli E
EE
Santamaria
Pere
P
Workman
Creg J
CJ
Vignali
Dario A A
DA
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000009:adverse effects*; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens; D011948:Receptors, Antigen, T-Cell; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2