NKG2As

NKG2A, also written as NKG2A, is an inhibitory receptor of the killer cell lectin-like receptor (KLR) family. It forms a receptor complex with CD94 to create the NKG2A/CD94 heterodimer. The receptor contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail, which, when engaged, recruits phosphatases such as SHP-1 and SHP-2 to dampen activation signals.

Ligand binding and signaling: The primary ligand for the NKG2A/CD94 complex is HLA-E, a non-classical MHC class I molecule. HLA-E presents peptides derived from leader sequences of classical MHC class I molecules. Interaction of NKG2A/CD94 with HLA-E delivers inhibitory signals to the cell bearing the receptor, reducing cytotoxicity and cytokine production by natural killer (NK) cells and certain CD8+ T cells.

Expression and function: NKG2A/CD94 is broadly expressed on most NK cells in humans and is found on a subset of CD8+ T cells, some γδ T cells, and decidual NK cells. The axis contributes to self-tolerance, NK cell education, and the regulation of immune responses against stressed, infected, or transformed cells.

Clinical relevance: In cancer, many tumors upregulate HLA-E to evade NK cell–mediated killing, making NKG2A/HLA-E signaling a target for immunotherapy. In chronic infections, sustained NKG2A expression can reflect a state of functional adaptation or exhaustion in NK and T cells. Therapeutically, blockade of NKG2A with monoclonal antibodies aims to unleash NK cell and CD8+ T cell–mediated responses. Monalizumab is a clinically investigated anti-NKG2A antibody, explored in combination regimens to enhance anti-tumor immunity.