[About salt and immunity-a story of Mr. Hyde : The influence of hyperosmolar microenvironment on immune response]

Hyperosmolar micromilieu has been observed in physiologic (kidney medulla, lymphatic tissue) and pathologic (renal allorejection, solid tumors) conditions. Hyperosmolarity can modulate gene expression and alter the stimulatory profile of macrophages and dendritic cells. We have reported that dendritic cells upon exposure to hypertonic stimuli shift their profile towards a macrophage-M2-like phenotype, resulting in attenuated local alloreactivity during acute kidney graft rejection. Moreover, we showed that a hyperosmotic microenvironment affects the cross-priming capacity of dendritic cells. Using ovalbumin as a model antigen, we showed that exposure of dendritic cells to hyperosmolarity strongly inhibits activation of antigen-specific T cells despite enhancement of antigen uptake, processing, and presentation; it can reduce dendritic cell-T cell contact time. We have identified TRIF as key mediator of this phenomenon. Moreover, we detected a hyperosmolarity-triggered, TRIF-dependent clustering of MHC class I‑antigen complexes, but not of unloaded MHCI molecules, providing a possible explanation for a reduced T cell activation. Our findings identify dendritic cells as important players in hyperosmolarity-triggered immune imbalance and suggest that targeting local hyperosmolarity in tumor micromilieu may contribute to an enhanced specific anti-tumor immune response.