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Infection with pathogens containing superantigens (Sags) can result in massive excessive CD4+ T cell activation and death in such conditions as toxic shock, food poisoning and autoimmune diseases. We here showed how enhancement of IL-6 signaling suppresses Sag-mediated activated CD4+ T cell death. Sag-induced CD4+ T cell death increased in IL-6 knockout (KO) mice, whereas it decreased in mice characterized by enhanced IL-6-gp130-STAT3 signaling. The serum concentration of IFN-gamma was inversely correlated with the magnitude of IL-6 signaling, and IFN-gamma deficiency inhibited Sag-induced activated CD4+ T cell death, suggesting that IL-6 suppresses CD4+ T cell death via IFN-gamma expression. Interestingly, depletion of activated CD8+ T cells inhibited Sag-mediated increases in IFN-gamma expression in IL-6 KO mice as well as the augmented CD4+ T cell death. The results demonstrate that IL-6-gp130-STAT3 signaling in activated CD8+ T cells contributes to Sag-induced CD4+ T cell death via IFN-gamma expression, highlighting this signaling axis in CD8+ T cells as a potential therapeutic target for Sag-related syndromes.

IFN-γ expression in CD8+ T cells regulated by IL-6 signal is involved in superantigen-mediated CD4+ T cell death