NKG2D signaling within the pancreas enhances CD8+ central memory T cell formation and decreases non-obese diabetic (NOD) diabetes development

Abstract

Abstract The immune receptor NKG2D is implicated in autoimmune diabetes. However, the mechanism by which NKG2D signaling affects diabetes is unclear. Among the aspects not known are 1) the relevant anatomical site(s) of NKG2D signaling, 2) the cells in which NKG2D signaling occurs and 3) whether NKG2D signaling enhances or inhibits diabetogenesis. These are among the critical questions that must be answered to determine whether modulation of NKG2D signaling could be used in intervention strategies in type 1 diabetes. To determine whether NKG2D signaling within the pancreatic islets modulates autoimmune diabetes, we generated a novel NOD mouse strain in which the mouse NKG2D ligand RAE1-e is constitutively expressed in the beta-islet cells (RIP-RAE1e mice). Insulitis progressed faster in RIP-RAE1e mice compared with control NOD mice. Despite this, there was a significant decrease in spontaneous diabetes in RIP-RAE1e mice compared with control mice. Using flow cytometry, we compared the immune cells present in the pancreas and spleen of pre-diabetic RIP-RAE1e and control NOD mice. Similar percentages and numbers of CD4+ T cells, CD8+ T cells and NK cells were detected. Similarly, equivalent numbers of CD69+ CD4+T and CD69+CD8+T cells were present. However, RIP-RAE1e mice contained increased numbers of CD44hiCD62Lhi (central memory T cell, Tcm, phenotype) CD8+ T cells and decreased numbers of CD44hiCD62Llo (effector/effector memory, Tem, phenotype) CD8+ T cells in both the pancreas and spleen. This increased Tcm:Teff/em ratio was not observed in the CD4+ T cell compartment. Together, these data demonstrate that NKG2D signaling within the pancreas drives an increased ratio of CD8+ Tcm:Teff/em cells and is protective against NOD diabetes.