Significance i NKT cells can both provide help and inhibit B cell responses. Our data show that when i NKT cells are activated with the glycolipid agonist αGalCer together with the inflammatory cytokine IL-18, they switch from regulating autoreactive B cells to promoting their expansion. As a consequence, autoreactive B cell responses remain unchecked by i NKT cells. The glycolipid αGalCer has been shown to have promising effects when administered as an adjuvant to achieve a better response to vaccines, as an antitumor agent, as well as in the regulation of autoimmunity. Our results highlight a facet of αGalCer-mediated i NKT cell activation in the context of inflammation and have broad implications for understanding the regulation of autoimmunity and use of αGalCer in therapy.