NKG2D signaling within the pancreas decreases NOD diabetes by enhancing CD8+ central memory T cell formation

Abstract

Abstract The main drivers of type 1 diabetes are islet-specific T cells. These cells must escape a myriad of tolerance mechanisms that control their activation in healthy individuals. One pathway implicated in this process is signaling through Natural Killer Group 2 member D (NKG2D). We demonstrate that the mRNAs encoding both NKG2D and NKG2D ligands are increased in the islets of patients with type 1 diabetes, making discerning the role of NKG2D-ligand interaction in the pancreas during diabetes development of significant interest. To this end, we developed a novel mouse model to determine the role of NKG2D specifically within the pancreas. This is a NOD mouse that expresses a transgene driving expression of the NKG2D ligand RAE1ɛ in islets (RIP-RAE1ɛ NOD mice). Spontaneous diabetes development was significantly decreased in RIP-RAE1ɛ-NOD mice compared with control NOD mice, and RIP-RAE1ɛ mice contained decreased numbers of CD44hiCD62Llo(effector/effector memory, Tem, phenotype) CD8+ T cells in both the pancreas and spleen. This decrease correlated with increased numbers of CD44hiCD62Lhi(central memory T cell, Tcm, phenotype) CD8+ T cells, which is a cell population previously demonstrated to contain cells that inhibit the CD8+ Teff response. Further, we found that NKG2D signaling in both NOD and human CD8+ T cells increased CD8+ Tcm differentiation in vitro. Together, these novel results suggest that the NKG2D pathway in CD8+ T cells could be utilized to inhibit type 1 diabetes progression.