Hyperosmolarity impedes the cross-priming competence of dendritic cells in a TRIF-dependent manner.
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.
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany. z.popovic@dkfz.de.|Institute of Pathology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany. z.popovic@dkfz.de.
Zoran V
ZV
Popovic
Department of Cellular Immunology, LIMES Institute, University of Bonn, Bonn, Germany.
Maria
M
Embgenbroich
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Federica
F
Chessa
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Viola
V
Nordström
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Mahnaz
M
Bonrouhi
Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
Thomas
0000-0003-1277-310X
T
Hielscher
Medical Research Center, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
Norbert
N
Gretz
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Shijun
S
Wang
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Daniel
D
Mathow
Department of Molecular Immunology and Cell Biology, LIMES Institute, University of Bonn, Bonn, Germany.
Thomas
T
Quast
Department of Membrane Biochemistry, LIMES Institute, University of Bonn, Bonn, Germany.
Jan-Gero
JG
Schloetel
Department of Molecular Immunology and Cell Biology, LIMES Institute, University of Bonn, Bonn, Germany.
Waldemar
W
Kolanus
Department of Cellular Immunology, LIMES Institute, University of Bonn, Bonn, Germany.
Sven
S
Burgdorf
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany. h.-j.groene@dkfz.de.
Hermann-Josef
HJ
Gröne
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D000941:Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D045142:Cross-Priming; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009997:Osmotic Pressure; D010047:Ovalbumin / Q000276:immunology
D033942:Adaptor Proteins, Vesicular Transport; D000941:Antigens; D015395:Histocompatibility Antigens Class I; D010047:Ovalbumin; C476286:Ticam1 protein, mouse