Killer cell lectin-like receptor subfamily C member 1 and Killer cell lectin-like receptor subfamily D member 1 receptor complex (CD94/NKG2A)

The CD94/NKG2A receptor complex is a heterodimeric inhibitory receptor primarily expressed on Natural Killer (NK) cells and a subset of CD8+ T cells (UniProt P26715, P49132). It consists of the CD94 (KLRD1) and NKG2A (KLRC1) subunits, which specifically recognize the non-classical MHC class I molecule HLA-E (PubMed: 9486650). This interaction functions as a critical immune checkpoint; when HLA-E binds to NKG2A, it triggers inhibitory signaling via immunoreceptor tyrosine-based inhibitory motifs (ITIMs), preventing NK cell activation and protecting healthy cells from lysis (PubMed: 29946152). In many cancers, HLA-E is overexpressed as a mechanism of immune evasion, effectively "switching off" the anti-tumor response of infiltrating NK and T cells (PubMed: 30503213). Therapeutic targeting of this complex, most notably with the monoclonal antibody monalizumab, blocks the NKG2A/HLA-E interaction to enhance the cytotoxic activity of the immune system against tumor cells (ClinicalTrials.gov: NCT02671435). This approach is currently being investigated in various clinical trials, often in combination with other checkpoint inhibitors like PD-1/PD-L1 blockers, to overcome resistance in solid tumors and hematologic malignancies (PubMed: 30503213). Beyond oncology, the CD94/NKG2A pathway is also relevant in viral infections where pathogens may upregulate HLA-E to escape immune detection. The complex is distinct from other NKG2 receptors, such as the activating NKG2C, which also pairs with CD94 but signals through different pathways. Monitoring the expression levels of both the receptor on immune cells and the ligand on target cells is essential for predicting therapeutic efficacy. Overall, CD94/NKG2A represents a promising next-generation immune checkpoint target for enhancing innate and adaptive anti-tumor immunity.

Other names

NKG2A/CD94KLRD1/KLRC1 complexCD94/NKG2A inhibitory receptorKP43/NKG2A

Immune checkpoint inhibition by blocking the interaction between the CD94/NKG2A receptor and its ligand HLA-E, thereby preventing inhibitory signaling and enhancing the anti-tumor activity of NK cells and CD8+ T cells (PubMed: 30503213).