Human natural killer (NK) cells are effectors of innate immunity, capable of killing transformed or virusinfected cells and producing pro-inflammatory cytokines, once activated in a non-HLA-dependent fashion. NK cells express receptors for HLA-I molecules, including CD8, or members of the Inhibitory Receptor Superfamily (IRS), such as the Killer Ig-like receptor (KIR) or C-Lectin type Inhibitory Receptor (CLIR). Soluble molecules of HLA-I (sHLA-I) are significantly increased in the serum of patients affected by auto-immune or infectious diseases. We reported that upon interaction of sHLA-I with either CD8 or IRS activating isoforms (AR), NK cells produced and released FasL which elicited NK cell apoptosis by interacting with Fas at the NK cell surface. CD94/NKG2A or KIR2DL, both inhibiting isoforms of IRS, exerted an inhibitory effect on sHLA-I-mediated apoptosis and secretion of FasL induced via CD8, suggesting that IRS can function as survival receptors. Moreover, large amounts of IFN-γ were detectable in culture supernatant of either CD8+ or AR+ NK cells incubated with the appropriate sHLA-I ligand. In chronic diseases, sHLA could amplify inflammation and, at the same time, eliminate effectors of innate immunity, thus favouring infections. On the other hand, this could represent a mechanism of down-regulation of NK-mediated functions as well, which ultimately contributes to limit self-reaction. Importantly, cyclosporin A (CsA) blocks both AR- or CD8-mediated apoptosis and IFN-γ production, without affecting AR-mediated activation of cytolysis. This would indicate that CsA, although being an immunosuppressive drug, can downregulate inflammation maintaining NK cell-dependent innate immunity, further supporting CsA treatment in autoimmune diseases.