Fig. 1.

The mechanism of NK activation and self-tolerance. A In healthy conditions, self-HLA class I molecules of healthy cells bind the inhibitory receptors of NK cells such as KIRs and NKG2A/CD94. Dominant inhibitory signaling suppressed the cytolytic ability of NK cells to make autologous healthy cells “licensed”. B The majority of tumor cells downregulate or lost their MHC-I molecule expression to escape from the immune cells attacking. This results in decreasing tumor ligands combining with inhibitory receptors of NK cells, thus NK cells are activated to secret perforin and granzyme to lyse tumor cells. C Overexpressed activating ligands on stressed cells engage with NK cell receptors, leading to superior activating signaling surpassing inhibitory signaling. As a result, NK cells transform into activation state and initiate cell lysing. D Antibody-dependent cell-mediated cytotoxicity, ADCC. The tumor-specific Fc fragment binds CD16 (FcγRIII) of NK cells, resulting in ADCC development. In addition to ADCC, other killing mechanisms of NK cells include death-receptor-mediated and perforin/granzyme-mediated killing activities