NKG2D‐ligands: Putting everything under the same umbrella can be misleading

Abstract

NKG2D is a key receptor for the activation of immune effector cells, mainly Natural Killer cells and T lymphocytes, in infection, cancer and autoimmune diseases. Since the detection of ligands for NKG2D in sera of cancer patients is, in many human models, indicative of prognosis, a large number of studies have been undertaken to improve understanding of the biology regulating this receptor and its ligands, with the aim of translating this knowledge into clinical practice. Although it is becoming clear that the NKG2D system can be used as a tool for diagnosis and manipulated for therapy, some questions remain open due to the complexity associated with the existence of a large number of ligands, each one of them displaying distinct biological properties. In this review, we have highlighted some key aspects of this system that differ between humans and mice, including the properties of NKG2D, as well as the genetic and biochemical complexity of NKG2D-ligands. All of these features affect the characteristics of the immune response exerted by NKG2D-expressing cells and are likely to be important factors in the clearance of a tumour or the development of autoimmunity. Implementation of more global analyses, including information on genotype, transcription and protein properties (cellular vs released to the blood stream) of NKG2D-ligands expressed in patients will be necessary to fully understand the links between this system and disease progression.

The Paradoxical Role of NKG2D in Cancer Immunity

“…However, a previous study showed an opposing role for IL-21 ( 98 ) in its capacity to enhance NKG2D-dependent tumor rejection in mice. This may be explained by additional signaling via mouse DAP12, which can pair with mouse NKG2D but not human NKG2D, highlighting the species-specific nature of NKG2D signaling ( 99 ). Thus, in model studies, it is possible that depending on the cytokine milieu, preferential activation of DAP10 versus DAP12 guides the outcome of NK cell activation toward cytokine release and/or cytotoxic activity ( 100 ).…”

“…Finally, the DEN-induced HCC model recapitulates similar features described in human hepatitis and HCC including: (i) elevated levels of NKG2D and NKG2D ligands, (ii) expression of NKG2D ligands on healthy tissue, (iii) evidence for a high CD8 + T cell infiltrate that correlates with tissue damage and HCC, and (iv) potential dysfunction in NK cell subsets. Although human and mouse NKG2D ligands differ ( 99 ), they have both evolved to be capable of binding strongly to NKG2D ( 134 ). Molecular modeling showed that the ligand-binding site of NKG2D is highly conserved between both species, with mouse NKG2D being capable of binding all the human ligands ( 135 ).…”

Immunoassays for scarce tumour-antigens in exosomes: detection of the human NKG2D-Ligand, MICA, in tetraspanin-containing nanovesicles from melanoma

“…A paradigm of a molecule released by tumour cells with immune modulation functions is MICA (MHC class I chain-related protein A), a protein belonging to stress-related molecules that bind to the activating immune receptor NKG2D (activating natural killer group 2D) expressed on all human NK and CD8 + T cells [ 16 ]. Soluble ligands for NKG2D, including MICA, have been found in serum from several types of cancer patients and, in humans, high levels of soluble NKG2D ligands generally correlate with higher tumor grade and worse prognosis [ 17 ].…”

Engineering of chimeric natural killer cell receptors to develop precision adoptive immunotherapies for cancer

“…All NKG2DL are structurally related to MHC class I molecules [17,[30][31][32][33]. The murine NKG2DL include the retinoic acid early transcript (RAET) 1 proteins (RAE1α-ε), murine UL16-binding protein-like transcript 1 (MULT1) and the minor histocompatibility proteins, H60a-c [32,34]. It is noteworthy that only the ULBP/RAET genes are humanmouse orthologues.…”