SEC2-induced superantigen and antitumor activity is regulated through calcineurin.

Once the TCR-SAg-MHC II ternary complex is established, it triggers a variety of intracellular signal transduction pathways, which provoke extreme responses in the immune system. However, the signaling events that involved in SAg-induced immune activation are not well understood. In this study, we demonstrated that the Ca(2+)/calcineurin (CaN)/nuclear factor of activated T cells (NFAT) signaling pathway was involved in SEC2-induced immune activation, and selective blockade of CaN by its inhibitor cyclosporine A (CsA) can completely inhibited the SEC2-induced T-cell stimulating potency. In addition, we selected an engineered SEC2 mutant named SAM-1 based on a series of biological activity tests, and our further studies on it not only confirmed that the CaN activity and gene transcription of its key substrates were proportional to the SEC2/SAM-1-induced T-cell stimulating potency, but also suggested that intensified Ca(2+)/CaN/NFAT signaling transduction induced by SAM-1 resulted in enhanced T-cell stimulating potency, production of cytokines and cytotoxicity, which finally elicit the improved antitumor activity of SAM-1 in vivo.