TY  - JOUR
A1  - Wu, Hao
A1  - Zhao, Xiufeng
A1  - Hochrein, Sophia M.
A1  - Eckstein, Miriam
A1  - Gubert, Gabriela F.
A1  - Knöpper, Konrad
A1  - Mansilla, Ana Maria
A1  - Öner, Arman
A1  - Doucet-Ladevèze, Remi
A1  - Schmitz, Werner
A1  - Ghesquière, Bart
A1  - Theurich, Sebastian
A1  - Dudek, Jan
A1  - Gasteiger, Georg
A1  - Zernecke, Alma
A1  - Kobold, Sebastian
A1  - Kastenmüller, Wolfgang
A1  - Vaeth, Martin
T1  - Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming
JF  - Nature Communications
N2  - T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.
KW  - cytotoxic T cells
KW  - infection
KW  - lymphocyte differentiation
KW  - translational research
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358052
VL  - 14
ER  - 
TY  - JOUR
A1  - Wu, Hao
A1  - Reimann, Sabine
A1  - Siddiqui, Sophiya
A1  - Haag, Rainer
A1  - Siegmund, Britta
A1  - Dernedde, Jens
A1  - Glauben, Rainer
T1  - dPGS Regulates the Phenotype of Macrophages via Metabolic Switching
JF  - Macromolecular Bioscience
N2  - The synthetic compound dendritic polyglycerol sulfate (dPGS) is a pleiotropic acting molecule but shows a high binding affinity to immunological active molecules as L‐/P‐selectin or complement proteins leading to well described anti‐inflammatory properties in various mouse models. In order to make a comprehensive evaluation of the direct effect on the innate immune system, macrophage polarization is analyzed in the presence of dPGS on a phenotypic but also metabolic level. dPGS administered macrophages show a significant increase of MCP1 production paralleled by a reduction of IL‐10 secretion. Metabolic analysis reveals that dPGS could potently enhance the glycolysis and mitochondrial respiration in M0 macrophages as well as decrease the mitochondrial respiration of M2 macrophages. In summary the data indicate that dPGS polarizes macrophages into a pro‐inflammatory phenotype in a metabolic pathway‐dependent manner.
KW  - infection
KW  - macrophage polarization
KW  - MCP1
KW  - metabolic switch
KW  - polyglycerol sulfates
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212711
VL  - 19
IS  - 12
ER  -