NKG2A/CD159a is an approximately 40 kDa transmembrane C-type lectin superfamily protein that inhibits innate immune system activation (1). Mouse NKG2A consists of a 70 amino acid (aa) cytoplasmic domain with two ITIM inhibitory motifs, a 23 aa transmembrane segment, and a 151 aa extracellular domain (ECD) with one C-type lectin domain (2). Within the ECD, mouse NKG2A shares 41% and 71% aa sequence identity with human and rat NKG2A, respectively. Alternative splicing generates additional isoforms with a 17 aa deletion in the extracellular juxtamembrane region or a substitution of that region plus the transmembrane segment. NKG2A is expressed on a subset of NK cells and CD8 ⁺ T cells (2-6) where it forms a covalent heterodimer with CD94 (5, 7, 8). NKG2A-CD94 heterodimers bind to the widely expressed nonclassical MHC-I molecule, HLA-E (Qa-1 ^b in mouse), which presents a peptide derived from the signal peptide of classical MHC-I molecules (2, 7). Triggering the NKG2A-CD94 complex inhibits the cytolytic activity of NK and CD8 ⁺ T cells (2, 3, 5, 6, 9). This enables the innate immune system to detect cells that express host MHC-I molecules and to protect them from NK cell mediated lysis. This mechanism is subverted by human cytomegalovirus which encodes a peptide that is homologous to the HLA-E binding peptide (10). HCMV infected cells up-regulate both HLA-E and NKG2A expression and utilize this peptide to escape from immune clearance (3, 10). In contrast, vaccinia virus induces HLA-E down-regulation, thus permitting NK cell lysis of the virally infected cell (11).