Project description:Depending on how an antigen is perceived, dendritic cells (DCs) mature in an immunogenic or tolerogenic manner, safeguarding the balance between immunity and tolerance. Whereas the pathways driving immunogenic maturation in response to infectious insults are well characterized, the signals driving tolerogenic maturation in homeostasis are still poorly understood. Here we demonstrate that engulfment of apoptotic cells triggers homeostatic maturation of conventional cDC1s in the spleen. This process can be modeled by engulfment of empty, non-adjuvanted lipid nanoparticles (LNPs), is marked by intracellular accumulation of cholesterol, and highly unique to type 1 DCs. Engulfment of apoptotic cells or cholesterol-rich LNPs leads to activation of the LXR pathway driving cellular cholesterol efflux and repression of immunogenic genes. In contrast, simultaneous engagement of TLR3 to mimic viral infection via administration of poly(I:C)-adjuvanted LNPs represses the LXR pathway, thus delaying cellular cholesterol efflux and inducing genes that promote T cell immunity. These data demonstrate how DCs exploit the conserved cellular cholesterol efflux pathway to regulate induction of tolerance or immunity and reveal that administration of non-adjuvanted cholesterol-rich LNPs is a powerful platform for inducing tolerogenic DC maturation.
Project description:Depending on how an antigen is perceived, dendritic cells (DCs) mature in an immunogenic or tolerogenic manner, safeguarding the balance between immunity and tolerance. Whereas the pathways driving immunogenic maturation in response to infectious insults are well characterized, the signals driving tolerogenic maturation in homeostasis are still poorly understood. Here we demonstrate that engulfment of apoptotic cells triggers homeostatic maturation of conventional cDC1s in the spleen. This process can be modeled by engulfment of empty, non-adjuvanted lipid nanoparticles (LNPs), is marked by intracellular accumulation of cholesterol, and highly unique to type 1 DCs. Engulfment of apoptotic cells or cholesterol-rich LNPs leads to activation of the LXR pathway driving cellular cholesterol efflux and repression of immunogenic genes. In contrast, simultaneous engagement of TLR3 to mimic viral infection via administration of poly(I:C)-adjuvanted LNPs represses the LXR pathway, thus delaying cellular cholesterol efflux and inducing genes that promote T cell immunity. These data demonstrate how DCs exploit the conserved cellular cholesterol efflux pathway to regulate induction of tolerance or immunity and reveal that administration of non-adjuvanted cholesterol-rich LNPs is a powerful platform for inducing tolerogenic DC maturation.
