NKG2A

NKG2A also known as CD159a is an inhibitory NK cell receptor that is part of the NKG2 family and encoded by the KLRC1 gene.
NKG2A is expressed predominantly by NK cells, but can also be found on a subset of T cells, especially on CD8⁺ cytotoxic T cells.

Structure and signaling

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

Ligand and function

Health

In humans, CD94/NKG2A receptors bind to the non-classical MHC class I molecule HLA-E. For proper binding, specific peptides presented on HLA-E are required.
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.

Virus infection

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 , 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.

Cancer

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.
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.