Weak Proinsulin Peptide–Major Histocompatibility Complexes Are Targeted in Autoimmune Diabetes in Mice

Abstract

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-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. h 4). 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.

Associations of human leukocyte antigens with autoimmune diseases: challenges in identifying the mechanism

“…[47][48][49] It was later found in both human and the NOD mice that insulin and other pancreatic self-peptides that were presented weakly on the susceptible HLA/major histocompatibility complex allele products were the targets of self-reactive T cells. [50][51][52][53][54][55][56] These studies established a notion that the T1D pathogenesis was mediated through the formation of unstable HLA/major histocompatibility complex-peptide complex. 57 The presence of non-Asp57β does not appear to be a prerequisite for the accommodation of self-peptides in a weak binding register.…”

Discovery of low-affinity preproinsulin epitopes and detection of autoreactive CD8 T-cells using combinatorial MHC multimers

“…In addition, these should be complemented by detection technologies suited to enumerate rare autoreactive T-cells within the limitations imposed by the blood volume obtained from children with, or atrisk of disease. Moreover, low-affinity HLA-binding peptides have been shown to play a role in autoimmunity [14]. As the avidity of the auto-immune TCR can be low [11], both factors may contribute to an increase in background, as observed in many of the current detection methods.…”

Cellular and molecular events in the localization of diabetogenic T cells to islets of Langerhans

“…One important feature was their very high content of peptide-MHC complexes derived from β-cell proteins in a process unrelated to β-cell death. These DCs were highly effective in presenting β-cell antigens to diabetogenic CD4 T cells ex vivo (13)(14)(15). It is also known that the lymph nodes draining the pancreas contain APC-bearing β-cell antigens (16,17) and are essential for the initiation of diabetes and the priming of CD4 T cells (i.e., diabetogenic CD4 T cells).…”