Pro- and anti-apoptotic fate decisions induced by di- and trimeric synthetic cytokine receptors

Synthetic strategies to activate cytokine receptors so far only address standard dimeric cytokine receptor assemblies. The 19 ligands of the tumor necrosis factor superfamily (TNFSF), however, form noncovalent trimers and receptor trimerization is considered to be essential for receptor activation. Synthetic TNFR1, TNFR2, and Fas/CD95 receptors were activated by synthetic trimeric ligands which induced NF-κB signaling or Caspase-induced apoptosis. Albeit dimeric receptor activation did not induce synthetic TNFR1 and TNFR2 signaling, dimeric FasL induced extenuated apoptosis. Simultaneous integration of dimeric Interleukin (IL-)6 receptor gp130 and trimeric Fas as synthetic cytokine receptors in one cell enabled binary cell fate decisions, gp130-mediated proliferation or Fas-mediated apoptosis. In summary, our modular fully synthetic cytokine signaling system allows precisely orchestrated cellular responses to selectively induce pro- and anti-apoptotic signaling via canonical dimeric receptors of the IL-6 family and non-canonical trimeric receptor complexes of the TNF superfamily.