Stress-induced natural killer cell ligands (NKG2DL)

Stress-induced natural killer (NK) cell ligands, including MHC class I polypeptide-related sequence A/B (MICA/B) and UL16-binding proteins (ULBPs), are cell surface proteins that are upregulated in response to cellular stress, such as malignant transformation, viral infection, or DNA damage [1, 5]. These ligands serve as critical recognition signals for the activating receptor NKG2D (KLRK1), which is expressed on NK cells, γδ T cells, and Natural Killer T (NKT) cells [1, 9]. In the context of engineered hematopoietic stem cell-derived NKT (HSC-NKT) cells, these ligands provide a secondary, antigen-independent mechanism for tumor recognition that complements the invariant T-cell receptor (iTCR) and any introduced chimeric antigen receptors (CARs) [1, 5]. This multi-targeted approach is particularly valuable for treating solid tumors, as it helps overcome immune evasion strategies like HLA downregulation or antigen loss [5, 8]. Therapeutic platforms, such as those developed by Appia Bio, utilize allogeneic HSC-engineered iNKT cells to leverage these interactions for "off-the-shelf" cancer immunotherapy [7, 8]. Other therapeutic strategies targeting these ligands include NKG2D-based CAR T cells and monoclonal antibodies designed to prevent ligand shedding [10]. Despite their potential, challenges such as the shedding of soluble ligands (sMICA/B) can act as decoys and inhibit immune responses [1, 4].

Other names

MICA/BULBPsMIC ligandsNKG2D ligandsStress-induced ligands

Recognition of stress-induced ligands by the activating receptor NKG2D on effector cells (NK, NKT, or T cells), triggering cytotoxic activity and cytokine production.