Abstract
Tissue osmolarity varies among different organs and can be considerably increased under pathologic conditions. Hyperosmolarity has been associated with altered stimulatory properties of immune cells, especially macrophages and dendritic cells. We have recently 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. Here, we examined how hyperosmotic microenvironment affects the cross-priming capacity of dendritic cells. Using ovalbumin as 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. We identified TRIF as key mediator of this phenomenon. Moreover, we detected a hyperosmolarity-triggered, TRIF-dependent clustering of MHCI loaded with the ovalbumin-derived epitope, but not of overall MHCI molecules, providing a possible explanation for a reduced T cell activation. Our findings identify dendritic cells as important players in hyperosmolarity-mediated immune imbalance and provide evidence for a novel pathway of inhibition of antigen specific CD8+ T cell response in a hypertonic micromilieu.
Highlights
MHCI-mediated antigen presentation is essential for an effective cytotoxic immune response against infected cells and tumor cells
Direct measurement of OTI cell proliferation went in line with cytokine secretion data (Fig. 1c), Interestingly, significant alterations in secretion of IFNγ were already observed at 370 mOsm, whereas clear differences in proliferation were only seen at 450 mOsm, pointing out that cytokine secretion might be more sensitive to the hypertonic conditions of the dendritic cells (DCs) than OTI proliferation
To examine the short-term effects of NaCl-enriched medium on bone marrow derived dendritic cells (BMDCs) differentiated in isotonic conditions, the cells were exposed to high salt solely during Ovalbumin grade VII (OVA) uptake, or alternatively during both OVA uptake and co-culture with OTI cells; in both cases a significant inhibition of cross-priming was evident (Fig. 1d), suggesting that long-term exposure of immature BMDCs is not necessary for its blocking effect on cross-priming
Summary
MHCI-mediated antigen presentation is essential for an effective cytotoxic immune response against infected cells and tumor cells. The efficacy of cross-presentation seems to be modulated by a variety of conditions, such as type of antigen, DC activation status, specific tissue environment and inflammatory stimuli[11, 12] It is still not known which microenvironmental signals may influence antigen processing and presentation by DC. We have detected that NaCl-hypertonic stress in both immunologically silent and pro-inflammatory micromilieus strongly inhibits the capacity of dendritic cells to activate CD8+ T cells in a TRIF-dependent, NFAT5-independent manner. This effect is potentially tuned by a complex set of events which result in surface MHCI-antigen cluster formation
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