Manipulating the NKG2D Receptor-Ligand Axis Using CRISPR: Novel Technologies for Improved Host Immunity

Abstract

The activating immune receptor natural killer group member D (NKG2D) and its cognate ligands represent a fundamental surveillance system of cellular distress, damage or transformation. Signaling through the NKG2D receptor-ligand axis is critical for early detection of viral infection or oncogenic transformation and the presence of functional NKG2D ligands (NKG2D-L) is associated with tumor rejection and viral clearance. Many viruses and tumors have developed mechanisms to evade NKG2D recognition via transcriptional, post-transcriptional or post-translational interference with NKG2D-L, supporting the concept that circumventing immune evasion of the NKG2D receptor-ligand axis may be an attractive therapeutic avenue for antiviral therapy or cancer immunotherapy. To date, the complexity of the NKG2D receptor-ligand axis and the lack of specificity of current NKG2D-targeting therapies has not allowed for the precise manipulation required to optimally harness NKG2D-mediated immunity. However, with the discovery of clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins, novel opportunities have arisen in the realm of locus-specific gene editing and regulation. Here, we give a brief overview of the NKG2D receptor-ligand axis in humans and discuss the levels at which NKG2D-L are regulated and dysregulated during viral infection and oncogenesis. Moreover, we explore the potential for CRISPR-based technologies to provide novel therapeutic avenues to improve and maximize NKG2D-mediated immunity.

Research progress in the mechanism of action of NK cell-related receptors during recurrent spontaneous abortion

“…The mutual recognition and cross-linking of the MIC molecule and the NKG2D receptor enable immune cells to recognize and attack the emerging stress cells externally. No MHC Class I expression or antigen recognition is required; Therefore, it can be said that the MIC/NKG2D interaction is an effective immune surveillance mechanism [37] .…”

Unpacking the Complexity of Epithelial Plasticity: From Master Regulator Transcription Factors to Non-Coding RNAs

“…Aside from MHC Class I, EMT-TFs have previously been shown to activate the inhibitory immune receptors killer Ig-like receptors (KIR) KIR3DL1, KIR2DL1, KIR2DL3, and KIR2DL4 [145], and repress activating immune-receptor natural killer group member D (NKG2D) ligands UL-16 binding protein (ULBP) 1 [146] and ULBP2 [147] on the tumor cell surface. Interestingly, Lopez-Soto and colleagues [147] showed that induction of EMT in colorectal cancer cells via SNAIL overexpression induced upregulation of the NKG2D ligands MICA/B and ULBP2, suggesting an avenue for NKG2D-mediated natural killer (NK) cell immunotherapy [148]. However, follow-up experiments identified that levels of soluble MICA were also elevated in the SNAIL-activated tumors, which act as a decoy to limit anti-cancer surveillance by NK cells.…”