NKG2D Immune Checkpoint Molecule for Drug Development

Overview of NKG2D

NKG2D immune checkpoint molecule is a part of immune checkpoints of NK cell. The NKG2D receptor, classified as a C-type lectin-like receptor, finds its expression on natural killer (NK) cells, γδ T cells, CD8+ T cells, as well as select autoreactive or immunosuppressive CD4+ T cells. This receptor stands as a pivotal recognition element, playing a central role in identifying and eradicating cells that have undergone damage, transformation, or infection by pathogens.

The NKG2D receptor is composed of a homodimer structure connected by disulfide bonds, which forms an association with a homodimer of DNAX-activating protein 10 (DAP10) to facilitate cellular signaling. NKG2D's ligands encompass MHC class-I polypeptide-related sequence A (MICA), MICB, and a set of six UL16-binding proteins (ULBP1-6). MICA/B molecules, also referred to as PERB11.1/11.2, share analogous structural and functional characteristics. Both molecules feature three extracellular domains (α1, α2, and α3), coupled with a transmembrane domain responsible for cell surface binding.

Architecture of the human NKG2D receptor and its corresponding ligands. (Alves, et al., 2021)Fig. 1 Architecture of the human NKG2D receptor and its corresponding ligands.1

Function and pertinent pathways associated with the NKG2D

  • Activation of the human NKG2D receptor triggers potent cytolytic responses that transcend inhibitory cues in NK cells. Additionally, it amplifies TCR-dependent activation in CD8+ T cells, Vγ2Vδ2, and gut intraepithelial Vγ1δ1 T cells. Furthermore, NKG2D's function is nuanced, it can deliver either a co-stimulatory signal or a direct activating signal contingent upon the cellular milieu and the initial influence of cytokine environments.
  • Diverse ligands possess the potential to incite distinct signaling pathways, leading to diverse trajectories of receptor internalization. Cellular reactions to allelic variants of NKG2D ligands vary, underscoring their role in inducing heterogeneous functional outcomes.

Function resulting from the engagement of NKG2D with distinct ligand/allelic variants. (Zingoni, et al., 2018)Fig. 2 Function resulting from the engagement of NKG2D with distinct ligand/allelic variants.2

  • Upon NKG2D engagement with its ligand, a cascade of molecular pathways is set into motion within NK cells, orchestrated by the DAP10 signaling molecule. The activation of NK cell cytotoxicity is facilitated through multiple channels, including the involvement of phospholipase C Gamma 2 (PLCγ2), c-Jun-NH (2)-terminal kinase (JNK), and phosphatidylinositol 3-hydroxy kinase PI3K. Notably, the release of cytotoxic granules is triggered by both the PLCγ2 and PI3K pathways. In parallel, the JAK-STAT5 (Janus kinase 2-Signal Transducer and Activator of Transcription 5) pathway is instrumental in eliciting cytokine release.

Initiation of NKG2D-associated signaling cascades. (Siemaszko, et al., 2021)Fig. 3 Initiation of NKG2D-associated signaling cascades.3

Case Study

The structure of bivalent and bispecific Fab-like antibodies. (Raynaud, et al., 2021) Fig. 4 The structure of bivalent and bispecific Fab-like antibodies.4
This study groundbreakingly introduces novel immunotherapeutics utilizing camelid-derived single-domain antibodies to effectively target NKG2D, thereby modulating NK cell functions.
The neutralization of NKG2D leads to a reduction in CD8+ T-cell cytotoxic activity. (Walsh, et al., 2008) Fig. 5 The neutralization of NKG2D leads to a reduction in CD8+ T-cell cytotoxic activity.5
These results showcase the operational significance of NKG2D in safeguarding the host against acute viral encephalitis. It achieves this by specifically augmenting cytotoxic T lymphocyte (CTL) efficacy through the infiltration of virus-targeting CD8(+) T cells.

Services at Creative Biolabs

Creative Biolabs offers comprehensive support across a broad spectrum of initiatives within the pharmaceutical frontier, specifically focused on advancing immune regulatory pathways. In the current landscape, we unveil a spectrum of customized resolutions dedicated to the NKG2D immune checkpoint domain, encompassing but not limited to the development of antibodies targeting immune checkpoints, the cultivation of small molecule drugs directed towards immune checkpoints, and the provision of immune checkpoint assays: immune checkpoint assays, immune checkpoint antibody development, biomarker development for immune checkpoint inhibitor (ICI).

We cordially invite our esteemed clients to contact us and share the particulars of your needs.


  1. Alves, Eric, et al. "Manipulating the NKG2D receptor-ligand axis using CRISPR: Novel technologies for improved host immunity." Frontiers in Immunology 12 (2021): 712722.
  2. Zingoni, Alessandra, et al. "NKG2D and its ligands:"one for all, all for one"." Frontiers in immunology 9 (2018): 476.
  3. Siemaszko, et al. "NKG2D natural killer cell receptor—a short description and potential clinical applications." Cells 10.6 (2021): 1420.
  4. Raynaud, Adeline, et al. "Anti-NKG2D single domain-based antibodies for the modulation of anti-tumor immune response." Oncoimmunology 10.1 (2021): 1854529.
  5. Walsh, et al. "NKG2D receptor signaling enhances cytolytic activity by virus-specific CD8+ T cells: evidence for a protective role in virus-induced encephalitis." Journal of virology 82.6 (2008): 3031-3044.

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