NKG2A

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.

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 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.

Studies on SARS-CoV-2 have shown that the viral Nsp13-Protein contains a peptide that is presented on HLA-E. Presentation of the viral peptide disrupts the binding to NKG2A and thus causes NK cell activation resulting in protective immune responses against infected cells. Moreover, the Omicron BQ.1 variant has acquired a mutation in this HLA-E-restricted peptide, which diminishes its presentation. This could be a clue that SARS-CoV-2 has evolutionarily adapted to NK cell responses.

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.