Weak proinsulin peptide–major histocompatibility complexes are targeted in autoimmune diabetes in mice
MG Levisetti, DM Lewis, A Suri, ER Unanue - Diabetes, 2008 - Am Diabetes Assoc
MG Levisetti, DM Lewis, A Suri, ER Unanue
Diabetes, 2008•Am Diabetes AssocOBJECTIVE—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 β-cell antigen epitope and T-cell autoreactivity in a model of
autoimmune diabetes. RESEARCH DESIGN AND METHODS—The binding of a proinsulin
epitope, proinsulin-1 (47–64)(PI-1 [47–64]), to the MHC class II molecules I-Ag7 and I-Ak …
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 β-cell antigen epitope and T-cell autoreactivity in a model of
autoimmune diabetes. RESEARCH DESIGN AND METHODS—The binding of a proinsulin
epitope, proinsulin-1 (47–64)(PI-1 [47–64]), to the MHC class II molecules I-Ag7 and I-Ak …
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 β-cell antigen epitope and T-cell autoreactivity in a model of autoimmune diabetes.
RESEARCH DESIGN AND METHODS—The binding of a proinsulin epitope, proinsulin-1(47–64) (PI-1[47–64]), to the MHC class II molecules I-Ag7 and I-Ak was measured using purified class II molecules. T-cell reactivity to the proinsulin epitope was examined in I-Ag7+ and I-Ak+ mice.
RESULTS—C-peptide epitopes bound very weakly to I-Ag7 molecules. However, C-peptide–reactive T-cells were induced after immunization in I-Ag7–bearing mice (NOD and B6.g7) but not in I-Ak–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 β-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.
Am Diabetes Assoc