Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, KS.
Department of Medicine, University of Tennessee, Memphis, TN.
Diabetes. 2020 Aug;69(8):1749-1762. doi: 10.2337/db19-0979. Epub 2020 Jun 13.
NKG2D is implicated in autoimmune diabetes. However, the role of this receptor in diabetes pathogenesis is unclear owing to conflicting results with studies involving global inhibition of NKG2D signaling. We found that NKG2D and its ligands are present in human pancreata, with expression of NKG2D and its ligands increased in the islets of patients with type 1 diabetes. To directly assess the role of NKG2D in the pancreas, we generated NOD mice that express an NKG2D ligand in β-islet cells. Diabetes was reduced in these mice. The reduction corresponded with a decrease in the effector to central memory CD8 T-cell ratio. Further, NKG2D signaling during in vitro activation of both mouse and human CD8 T cells resulted in an increased number of central memory CD8 T cells and diabetes protection by central memory CD8 T cells in vivo. Taken together, these studies demonstrate that there is a protective role for central memory CD8 T cells in autoimmune diabetes and that this protection is enhanced with NKG2D signaling. These findings stress the importance of anatomical location when determining the role NKG2D signaling plays, as well as when developing therapeutic strategies targeting this pathway, in type 1 diabetes development.
NKG2D 与自身免疫性糖尿病有关。然而，由于涉及 NKG2D 信号通路的全局抑制的研究结果相互矛盾，因此该受体在糖尿病发病机制中的作用尚不清楚。我们发现 NKG2D 及其配体存在于人类胰腺中，1 型糖尿病患者胰岛中 NKG2D 及其配体的表达增加。为了直接评估 NKG2D 在胰腺中的作用，我们生成了在β胰岛细胞中表达 NKG2D 配体的 NOD 小鼠。这些小鼠的糖尿病发病减少。这种减少与效应器至中央记忆 CD8 T 细胞的比例降低相对应。此外，在体外激活小鼠和人 CD8 T 细胞期间，NKG2D 信号导致体内中央记忆 CD8 T 细胞数量增加，并保护糖尿病。总之，这些研究表明，中央记忆 CD8 T 细胞在自身免疫性糖尿病中具有保护作用，而 NKG2D 信号增强了这种保护作用。这些发现强调了当确定 NKG2D 信号通路在 1 型糖尿病发展中的作用以及开发针对该通路的治疗策略时，解剖位置的重要性。
