NKG2A

NKG2A is an inhibitory receptor of the NKG2 family that forms a heterodimer with CD94 to create the functional receptor CD94/NKG2A on natural killer (NK) cells and some cytotoxic T cells. In humans, the gene KLRC1 encodes NKG2A. The receptor is part of the CD94/NKG2A complex expressed on NK cells and certain T cell subsets.

NKG2A recognizes HLA-E, a non-classical MHC class I molecule that presents peptides derived from the leader sequences of other HLA class I molecules. Engagement of HLA-E by CD94/NKG2A transmits inhibitory signals to the NK cell through ITIM motifs in the NKG2A cytoplasmic tail, which recruit SHP-1 and SHP-2 phosphatases and dampen activation signals from other receptors. This axis helps regulate NK cell activity and maintain self-tolerance, limiting unintended cytotoxicity.

Expression patterns vary with development and activation. Most NK cells express NKG2A, though expression can change as cells mature or respond to infection or expansion of other receptor subsets. NKG2A is also found on subsets of CD8+ T cells and NKT cells, where it can modulate cytotoxic responses.

Clinical relevance centers on immune evasion and immunotherapy. Some tumors and infected cells upregulate HLA-E to inhibit NK and T cell responses via NKG2A. Therapeutic blockade of NKG2A with monoclonal antibodies (for example, monalizumab) seeks to relieve this inhibition and enhance anti-tumor and antiviral immunity, often in combination with other therapies such as PD-1/PD-L1 inhibitors. Research continues to define NKG2A’s roles in infection, transplantation, and cancer treatment.