NKG2A

NKG2A also known as CD159a (Cluster of Differentiation 159a) is an inhibitory NK cell receptor that is part of the NKG2 family and encoded by the KLRC1 gene.^[1] NKG2A is expressed predominantly by NK cells, but can also be found on a subset of T cells, especially on CD8⁺ cytotoxic T cells.^[2][3]

NKG2A forms heterodimers with CD94 via disulfide bonds and assembles into a transmembrane protein type II. NKG2A contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic tail. When the CD94/NKG2A receptor binds to its ligands (see below), these ITIMs initiate a signalling cascade of tyrosine phosphatases, which suppresses NK cell activity.

In humans, CD94/NKG2A receptors bind to the non-classical MHC class I molecule HLA-E.^[4] For proper binding, specific peptides presented on HLA-E are required.^[5] Since the primary function of HLA-E is to present signal peptides derived from classical MHC class I molecules such as HLA-A, HLA-B or HLA-C, NKG2A allows immune cells to indirectly monitor the expression levels of HLA-A/B/C through complexes of HLA-E and signal peptides. Given that HLA-E is broadly expressed throughout the body, the receptor–ligand interactions of the NKG2A–HLA-E/pHLA axis maintains tolerance to self and ensures suppression of autoimmunity.

Certain viruses such as Cytomegalovirus attempt to escape from T cell-mediated immune responses by down-regulating HLA class I molecules including HLA-A, HLA-B or HLA-C. In this case, signal peptides from these HLA molecules are no longer available for presentation on HLA-E. This disrupts the interaction between CD94/NKG2A and HLA-E, leading to loss-of-inhibition of NKG2A-expressing NK cells. As a consequence, NKG2A⁺ NK cells recognize CMV-infected cells through a mechanism termed missing self. To counteract this recognition, CMV contains the glycoprotein UL40, which provides a viral peptide that mimicks the sequence of self peptides from HLA molecules and is presented on HLA-E. As a result, CD94/NKG2A binds to HLA-E/pUL40, NKG2A⁺ NK cells remain inhibited, and the virus achieves immune escape.^[6]

In the context of cancer, NKG2A has been identified as important immune checkpoint. HLA-E is highly expressed across multiple cancer types, preventing adequate immune responses by NKG2A-expressing NK cells and cytotoxic T cells.^[7] Similar to other checkpoint inhibitors, the blocking anti-NKG2A antibody monalizumab is currently in clinical testing with the goal to revert NKG2A-dependent inhibition and to unleash immune responses against the cancer.^[8]

• CD94/NKG2
• KLRC2
• NKG2D