Killer cell lectin-like receptor subfamily C member 1 – HLA class I antigen alpha chain E complex (NKG2A/HLA-E)

The NKG2A–HLA-E axis is a critical inhibitory immune checkpoint that regulates the activity of natural killer (NK) cells and a subset of cytotoxic CD8+ T cells [1.3.2, 1.3.5]. NKG2A, also known as Killer cell lectin-like receptor subfamily C member 1, forms a heterodimer with CD94 to recognize HLA-E, a non-classical MHC class I molecule that typically presents leader sequence peptides from other HLA molecules [1.1.1, 1.2.4]. Under physiological conditions, this interaction serves to protect healthy cells from immune-mediated lysis by signaling through immunoreceptor tyrosine-based inhibitory motifs (ITIMs) [1.2.1, 1.4.2]. However, many cancers exploit this pathway by overexpressing HLA-E, thereby evading immune detection and suppressing the effector functions of tumor-infiltrating lymphocytes [1.1.3, 1.2.2]. Therapeutic targeting of this axis, primarily through monoclonal antibodies like monalizumab, aims to disrupt the inhibitory signal and restore the immune system's ability to eliminate malignant cells [1.2.3, 1.3.1]. This approach is currently being investigated in various solid and hematologic malignancies, often in combination with other checkpoint inhibitors or targeted therapies [1.1.1, 1.3.2]. Beyond cancer, the axis is also relevant in viral infections and the prevention of autoimmune diseases [1.3.5, 1.4.1]. The peptide-sensitive nature of the HLA-E/NKG2A interaction adds a layer of complexity to its regulation and therapeutic potential [1.2.4].

Other names

NKG2ACD159aKLRC1HLA-EMHC class I antigen ECD94/NKG2AQa-1b (mouse ortholog)

Immune checkpoint inhibition by blocking the interaction between the inhibitory receptor NKG2A (on NK and T cells) and its ligand HLA-E (on target cells), thereby restoring cytotoxic activity and enhancing anti-tumor immunity [1.2.2, 1.3.2].