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 C. albicans infection and fungal clearance. While CD137 signaling is critical in fungal clearance by increasing the phagocytic activity of neutrophils, CD137L signaling is indispensable for monocyte/macrophage-mediated inflammatory responses leading to mortality. Furthermore, our results reveal that CD25^hiCD4⁺ T cells stimulate macrophages to induce 'cytokine storm' through CD137L signaling. Moreover, we demonstrate that CD137 agonism has dual beneficial effects on renal tissue protection during C. albicans infection by promoting both resistance (fungal clearance) and tolerance (anti-inflammatory cytokine responses). In sum, our results identify a novel mechanism of anti-fungal immunity that is regulated by distinct signaling pathways delivered bi-directionally via the costimulatory receptor and ligand pair, CD137 and CD137L.

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