Invasive fungal infections by Candida albicans frequently cause mortality in immunocompromised patients, yet the cellular processes leading to this mortality remain ill-defined. Here, using genetic and immunological tools to probe functions of CD137 and its ligand (CD137L), we elucidate cellular and signaling mechanisms that are important in initiating inflammatory responses triggered by Candida albicans infection. While CD137 signaling is critical in fungal clearance by increasing the phagocytic activity of neutrophils, CD137L signaling is indispensible for macrophage-mediated inflammatory responses leading to mortality. Furthermore, our results reveal that CD137-expressing CD4⁺ regulatory T cells stimulate macrophages to induce cytokine storm through CD137L. Moreover, we demonstrate that CD137 agonism has dual beneficial effects during Candida albicans infection by reducing cytokine responses and organ damage and promoting fungal clearance. In sum, our results identify a novel mechanism of anti-fungal immunity that is regulated by distinct signaling pathways delivered bidirectionally via a receptor and ligand pair.

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