Killer-cell immunoglobulin-like receptor and NKG2A (Natural killer group 2 member A) (KIR/NKG2A)

This target complex refers to the inhibitory signaling axis between self-cells and Natural Killer (NK) cells, which is a critical component of immune self-tolerance and tumor evasion. MHC class I molecules, such as HLA-E and HLA-C, are expressed on the surface of healthy cells to signal 'self' to the immune system, but they are often upregulated by tumor cells to escape destruction (André et al., 2018, Cell). These ligands are recognized by inhibitory receptors on peripheral blood NK (PBNK) cells, specifically Killer-cell Immunoglobulin-like Receptors (KIR) and the CD94/NKG2A heterodimer (Purdy and Campbell, 2009, J. Immunol.). When these receptors bind their respective MHC-I ligands, they transmit inhibitory signals via Immunoreceptor Tyrosine-based Inhibitory Motifs (ITIMs) that prevent NK cell activation and the subsequent lysis of the target cell. In oncology, this interaction acts as an immune checkpoint similar to the PD-1/PD-L1 axis, effectively 'turning off' the innate immune response against the tumor (Borst et al., 2020, Nat. Rev. Immunol.). Therapeutic strategies involve using monoclonal antibodies like monalizumab (targeting NKG2A) or lirilumab (targeting KIR) to disrupt this binding. By blocking these inhibitory signals, the drugs restore the natural cytotoxic potential of NK cells and certain CD8+ T cells to recognize and eliminate malignant cells.

Other names

Inhibitory NK cell receptorsNK cell checkpointsCD158CD94/NKG2A complexMHC class I-recognizing inhibitory receptorsKiller cell lectin-like receptor C1

Monoclonal antibodies block the interaction between inhibitory receptors (KIR or NKG2A) on NK cells and their MHC class I ligands (such as HLA-C or HLA-E) on target cells, preventing inhibitory signaling and restoring NK cell-mediated cytotoxicity.