Glucagon‐reactive islet‐infiltrating CD8 T cells in NOD mice

Abstract

SummaryType 1 diabetes is characterized by T-cell-mediated destruction of the insulin-producing b cells in pancreatic islets. A number of islet antigens recognized by CD8 T cells that contribute to disease pathogenesis in nonobese diabetic (NOD) mice have been identified; however, the antigenic specificities of the majority of the islet-infiltrating cells have yet to be determined. The primary goal of the current study was to identify candidate antigens based on the level and specificity of expression of their genes in mouse islets and in the mouse b cell line MIN6. Peptides derived from the candidates were selected based on their predicted ability to bind H-2K d and were examined for recognition by islet-infiltrating T cells from NOD mice. Several proteins, including those encoded by Abcc8, Atp2a2, Pcsk2, Peg3 and Scg2, were validated as antigens in this way. Interestingly, islet-infiltrating T cells were also found to recognize peptides derived from proglucagon, whose expression in pancreatic islets is associated with a cells, which are not usually implicated in type 1 diabetes pathogenesis. However, type 1 diabetes patients have been reported to have serum autoantibodies to glucagon, and NOD mouse studies have shown a decrease in a cell mass during disease pathogenesis. Our finding of isletinfiltrating glucagon-specific T cells is consistent with these reports and suggests the possibility of a cell involvement in development and progression of disease.

T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes

“…One possibility is that, over time, some T1D patients develop autoreactivity against glucagon-producing alpha cells. Glucagon-reactive CD8 T cells have been identified in NOD mice ( 140 ); therefore we speculate that some individuals with T1D may develop autoimmunity against alpha cells over time. Glucagon acts in opposition to insulin, promoting glycogen breakdown in the liver and therefore promoting increased blood glucose levels.…”

“…If glucagon-derived peptides are associated with inflammation and cell death within the pancreas, existing autoreactive T cells could become primed in pancreas-draining lymph nodes, proliferate, and mediate destruction of glucagon-producing cells. In fact, there is emerging evidence that a small proportion of T1D patients develop antiglucagon antibodies ( 140 ). Another possibility is that destruction of autonomic innervation within pancreatic islets ( 141 ) leads to impaired communication with the hypothalamus, so that glucagon is not produced when signals are present based on blood glucose levels.…”

Characterization of the peptide binding specificity of the HLA class I alleles B*38:01 and B*39:06

“…We also note previous data from our group indicating that, in the case of infectious diseases, the majority of epitopes can be identified by selecting peptides scoring in the top 1–2% of all peptides (Moutaftsi et al 2006). We have also identified epitopes targeted by autoreactive CD8 T cells based on predicted binding affinities (Mukherjee et al 2015). Thus, our report of quantitative peptide-binding motifs for B*38:01 and B*39:06 should facilitate the identification of T cell epitopes derived either from autoantigens or from microbes.…”

Detection of vasostatin-1-specific CD8+ T cells in non-obese diabetic mice that contribute to diabetes pathogenesis

“…The presence of other CD8 1 T cells reactive to pancreatic cells has been reported [22], although these are not specific to the islet antigens and their clinical relevance in process of type 1 diabetes development remains to be determined.…”

“…In NOD mice, another diabetogenic CD8 1 T cell population recognizes H2-D brestricted epitopes, insulin A14-20 peptide [20] and a sequence from dystrophia myotonica kinase (DMK) protein, DMK 138-146 [21]. The presence of other CD8 1 T cells reactive to pancreatic cells has been reported [22], although these are not specific to the islet antigens and their clinical relevance in process of type 1 diabetes development remains to be determined.…”