New Insights Into the Regulation of Natural-Killer Group 2 Member D (NKG2D) and NKG2D-Ligands: Endoplasmic Reticulum Stress and CEA-Related Cell Adhesion Molecule 1

Abstract

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 via 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.

Keywords: CEA-related cell adhesion molecule 1; UL16 binding protein 1; endoplasmic reticulum stress; murine UL16-binding protein like transcript 1; natural-killer group 2 member D; natural-killer group 2 member D-ligand.

Figure 1

Endoplasmic reticulum (ER) stress-inducing murine UL16-binding protein like transcript 1 (MULT1) in mouse. MULT1 [encoded by UL16 binding protein 1 (Ulbp1)], but not other natural-killer group 2 member D (NKG2D)-ligands, mRNA, and surface expression are upregulated on ER-stressed mouse small intestinal epithelial cells. This occurs through activating factor 4 (ATF4) and/or C/EBP homologous protein (CHOP) presumably downstream of the protein kinase RNA-like ER kinase pathway. CHOP as a transcription factor binds directly to the promoter area of Ulbp1, which upon expression subsequently activates NKG2D-expressing intraepithelial group 1 innate lymphoid cells (ILCs) [natural killer (NK) cells and ILC1] that accumulate within the intestinal epithelium and promote small intestinal inflammation.

Figure 2

CEA-related cell adhesion molecule 1 (CEACAM1) regulating natural-killer group 2 member D (NKG2D)-ligands expression and NKG2D function. CEACAM1 regulates glycosylation of NKG2D-ligands, resulting in downregulation of the NKG2D-ligand expression on the cell surface of the tumor cell. CEACAM1 induced by interleukin-2 inhibits NKG2D-mediated cytotoxic function through recruitment of Src homology phosphatase 1 (SHP1) to phosphorylated CEACAM1 which leads to dephosphorylation of Vav1 on the natural killer (NK) cell. CEACAM1 on the NK cell and tumor cell interact homophilically through the N-domain of CEACAM1.