Hosomi Shuhei, Grootjans Joep, Huang Yu-Hwa, Kaser Arthur, Blumberg Richard S
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Front Immunol. 2018 Jun 18;9:1324. doi: 10.3389/fimmu.2018.01324. eCollection 2018.
Natural-killer group 2 member D (NKG2D) is a well-characterized activating receptor expressed by natural killer (NK) cells, NKT cells, activated CD8 T cells, subsets of γδ T cells, and innate-like T cells. NKG2D recognizes multiple ligands (NKG2D-ligands) to mount an innate immune response against stressed, transformed, or infected cells. NKG2D-ligand surface expression is tightly restricted on healthy cells through transcriptional and post-transcriptional mechanisms, while transformed or infected cells express the ligands as a danger signal. Recent studies have revealed that unfolded protein response pathways during endoplasmic reticulum (ER) stress result in upregulation of ULBP-related protein the protein kinase RNA-like ER kinase-activating factor 4-C/EBP homologous protein (PERK-ATF4-CHOP) pathway, which can be linked to the pathogenesis of autoimmune diseases. Transformed cells, however, possess mechanisms to escape NKG2D-mediated immune surveillance, such as upregulation of carcinoembryonic antigen (CEA)-related cell adhesion molecule 1 (CEACAM1), a negative regulator of NKG2D-ligands. In this review, we discuss mechanisms of NKG2D-ligand regulation, with a focus on newly discovered mechanisms that promote NKG2D-ligand expression on epithelial cells, including ER stress, and mechanisms that suppress NKG2D-ligand-mediated killing of cancer cells, namely by co-expression of CEACAM1.
自然杀伤细胞2族成员D（NKG2D）是一种特征明确的激活受体，由自然杀伤（NK）细胞、NKT细胞、活化的CD8 T细胞、γδ T细胞亚群以及固有样T细胞表达。NKG2D识别多种配体（NKG2D配体），以对应激、转化或感染的细胞发起固有免疫应答。通过转录和转录后机制，NKG2D配体在健康细胞表面的表达受到严格限制，而转化或感染的细胞则将这些配体作为危险信号进行表达。最近的研究表明，内质网（ER）应激期间的未折叠蛋白反应途径会导致ULBP相关蛋白上调，即蛋白激酶RNA样内质网激酶激活因子4-C/EBP同源蛋白（PERK-ATF4-CHOP）途径，这可能与自身免疫性疾病的发病机制有关。然而，转化细胞具有逃避NKG2D介导的免疫监视的机制，例如上调癌胚抗原（CEA）相关细胞黏附分子1（CEACAM1），它是NKG2D配体的负调节因子。在这篇综述中，我们讨论了NKG2D配体的调节机制，重点关注促进上皮细胞上NKG2D配体表达的新发现机制，包括内质网应激，以及抑制NKG2D配体介导的癌细胞杀伤的机制，即通过CEACAM1的共表达。
