CD94NKG2A

CD94/NKG2A is a heterodimeric inhibitory receptor expressed mainly on natural killer (NK) cells and some cytotoxic T cell subsets. It consists of the CD94 (KLRD1) subunit and the NKG2A (KLRC1) subunit; NKG2A provides the intracellular signaling module, while CD94 participates in ligand recognition. The receptor forms part of the human NK cell receptor repertoire that helps distinguish healthy cells from stressed or abnormal cells.

The ligand for CD94/NKG2A is HLA-E, a non-classical MHC class I molecule. HLA-E presents peptides derived from the leader sequences of classical MHC class I molecules. Engagement of HLA-E by the CD94/NKG2A receptor delivers an inhibitory signal to the NK cell, reducing its cytotoxic response. The NKG2A cytoplasmic tail contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit phosphatases such as SHP-1 and SHP-2 to dampen activation signals and inhibit processes like degranulation and cytokine production.

Expression of CD94/NKG2A is highest on NK cells, but it is also found on certain CD8+ T cells and other lymphocytes. Its surface level can be modulated by cellular context, including infection, cancer, and inflammatory cues. In health, the receptor contributes to self-tolerance by preventing NK cell attack against HLA-E–expressing normal cells; in disease, altered HLA-E expression by tumors or virally infected cells can modulate NK cell activity.

Clinical relevance is evolving. Blocking CD94/NKG2A with monoclonal antibodies (for example, anti-NKG2A agents in clinical trials) aims to enhance anti-tumor immunity, often in combination with other immunotherapies such as PD-1/PD-L1 inhibitors. The approach is under investigation for various cancers and transplantation contexts.