Weak proinsulin peptide-major histocompatibility complexes are targeted in autoimmune diabetes in mice.
OBJECTIVE
Weak major histocompatibility complex (MHC) binding of self-peptides has been proposed as a mechanism that may contribute to autoimmunity by allowing for escape of autoreactive T-cells from the thymus. We examined the relationship between the MHC-binding characteristics of a beta-cell antigen epitope and T-cell autoreactivity in a model of autoimmune diabetes.


METHODS
The binding of a proinsulin epitope, proinsulin-1(47-64) (PI-1[47-64]), to the MHC class II molecules I-A(g7) and I-A(k) was measured using purified class II molecules. T-cell reactivity to the proinsulin epitope was examined in I-A(g7+) and I-A(k+) mice.


RESULTS
C-peptide epitopes bound very weakly to I-A(g7) molecules. However, C-peptide-reactive T-cells were induced after immunization in I-A(g7)-bearing mice (NOD and B6.g7) but not in I-A(k)-bearing mice (B10.BR and NOD.h4). T-cells reactive with the PI-1(47-64) peptide were found spontaneously in the peripancreatic lymph nodes of pre-diabetic NOD mice. These T-cells were activated by freshly isolated beta-cells in the presence of antigen-presenting cells and caused diabetes when transferred into NOD.scid mice.


CONCLUSIONS
These data demonstrate an inverse relationship between self-peptide-MHC binding and T-cell autoreactivity for the PI-1(47-64) epitope in autoimmune diabetes.
Levisetti
Matteo G
MG
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. mleviset@im.wustl.edu
Lewis
Danna M
DM
Suri
Anish
A
Unanue
Emil R
ER
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011384:Proinsulin / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology*
D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D011384:Proinsulin