S101, an Inhibitor of Proliferating T Cells, Rescues Mice From Superantigen-Induced Shock

S101, a novel inhibitor of proliferating T cells, protects against superantigen-induced cytokine storm and toxic shock in a severe mouse model. S101 inhibits T-cell receptor and aryl hydrocarbon receptor signaling, preventing T-cell hyperactivation, and can be developed for clinical treatment of toxic shock. Abstract Superantigens (SAgs) are extremely potent bacterial toxins, which evoke a virulent immune response, inducing nonspecific T-cell proliferation, rapid cytokine release, and lethal toxic shock, for which there is no effective treatment. We previously developed a small molecule, S101, which potently inhibits proliferating T cells. In a severe mouse model of toxic shock, a single injection of S101 given together with superantigen challenge rescued 100% of the mice. Even when given 2 hours after challenge, S101 rescued 40% of the mice. S101 targets the T-cell receptor, inflammatory response, and actin cytoskeleton pathways. S101 inhibits the aryl hydrocarbon receptor, a ligand-activated transcription factor that is involved in the differentiation of T-helper cells, especially Th17, and regulatory T cells. Our results provide the rationale for developing S101 to treat superantigen-induced toxic shock and other pathologies characterized by T-cell activation and proliferation.