Triggering of CD8 as well as of the activating isoforms (AR) of Killer Ig-like receptor (KIR2DS) or C-Lectin type Inhibitory Receptor (CLIR) (CD94/NKG2) by their natural ligands, represented by soluble HLA-I (sHLA-I) isolated either from serum of healthy donors or from HLA-I 721.221 lymphoblastoid cell line transfected with appropriate HLA-I molecules, leads to NK cell apoptosis. Upon interaction of sHLA-I with either CD8 or AR for HLA-I, NK cells produced and released FasL which in turn elicited to NK cell apoptosis by interacting with Fas at the NK cell surface. Blocking anti-Fas mAb, as well as anti-FasL mAb, inhibited sHLA-I-mediated apoptosis in either CD8+ or AR⁺ NK cell clones. Importantly, AR-, as well as CD8-mediated apoptosis was down-regulated by NK cell treatment with cyclosporin A (CsA) while this drug had no effect on AR-mediated activation of cytolysis. This finding suggests that AR-mediated apoptosis and cytolysis can use different intracellular pathways. Furthermore, a large amount of IFN-γ was detectable in culture supernatant of either CD8⁺ or AR⁺ NK cells incubated with the appropriate sHLA-I ligand. Again, NK cell treatment with CsA strongly reduced IFN-γ production through the engagement of CD8 or AR for HLA-I. Finally, CD94/NKG2A complex or KIR2DL, classical members of the Inhibitory Receptor Superfamily (IRS), exerted an inhibitory effect on sHLA-I-mediated apoptosis and secretion of FasL induced via CD8. These findings suggest that interaction between sHLA-I and CD8 evokes an apoptotic signal which is down-regulated by IRS that function as survival receptors in NK cells.

Thus, human NK cells can undergo apoptosis via two distinct surface sHLA-I receptors: CD8, a receptor which recognizes a common portion of HLA-I, and AR isoforms of KIR and/or CLIR recognizing unique HLA-I alleles. The potential role of this apoptosis in regulating innate immune responses as well as autoimmune diseases will be discussed.