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

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-γ was inversely correlated with the magnitude of IL-6 signaling, and IFN-γ deficiency inhibited Sag-induced activated CD4⁺ T cell death, suggesting that IL-6 suppresses CD4⁺ T cell death via IFN-γ expression. Interestingly, depletion of activated CD8⁺ T cells inhibited Sag-mediated increases in IFN-γ 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-γ expression, highlighting this signaling axis in CD8⁺ T cells as a potential therapeutic target for Sag-related syndromes.