Dimethyl fumarate suppresses Tc17 cell fate in autoimmunity via ROS accumulation

Dimethyl fumarate (DMF) is approved for treatment of relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory disease of the central nervous system (CNS) that is caused by autoreactive T cells. The effect mechanism of DMF is not fully elucidated so far; however, a preferential impact on CD8+ T cells was described. In the cerebrospinal fluid (CSF) of MS patients IL-17-producing CD8+ T (Tc17) cells are enriched. In addition, during experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis (MS), a co-pathogenic function of Tc17 was described. Hence, Tc17 cells crucially contribute to autoimmune processes in the CNS of men and mice. This study shows that DMF elevated reactive oxygen species (ROS) in CD4+ T (Th17) cells and Tc17 cells by glutathione depletion, resulting in IL-17 suppression particularly in Tc17 cells. Accordingly, IL-17 production by CD8+ but not by CD4+ T cells was reduced in DMF-treated MS patients and DMF application diminished Tc17 cell pathogenicity in EAE. Accumulated ROS shifts the Tc17 transcriptome towards a cytotoxic T lymphocyte (CTL)-like signature by enhancing IL-2 signalling including phosphoinositide-3-kinase (PI3K)/ protein kinase B (AKT) and signal transducer and activator of transcription (STAT)5 pathways. AKT deactivated forkhead-box-Protein O (FOXO)1 leading to the upregulation of the transcription factor T-box transcription factor TBX21 (T-bet), which in turn suppressed IL-17. The modified transcriptional network was accompanied by altered histone modifications at the Il17 locus. In line, T-bet-deficiency, inhibition of histone deacetylases (HDAC), PI3K/AKT or STAT5 partially prevented DMF-mediated suppression of Tc17 cells. Thus, this work provides mechanistic insights into the selective modulation of Tc17 cell differentiation by DMF-mediated upregulation of ROS and IL-2 signalling with relevance for Tc17-driven pathologies including MS and psoriasis

IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis

IL-17-producing CD8+ (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC-to-TBX21, along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8+ T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, thereby limiting IL-17 and RORγt expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond

Dimethyl fumarate suppresses Tc17 cell fate in autoimmunity via ROS accumulation

Dimethyl fumarate (DMF) is approved for treatment of relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory disease of the central nervous system (CNS) that is caused by autoreactive T cells. The effect mechanism of DMF is not fully elucidated so far; however, a preferential impact on CD8+ T cells was described. In the cerebrospinal fluid (CSF) of MS patients IL-17-producing CD8+ T (Tc17) cells are enriched. In addition, during experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis (MS), a co-pathogenic function of Tc17 was described. Hence, Tc17 cells crucially contribute to autoimmune processes in the CNS of men and mice. This study shows that DMF elevated reactive oxygen species (ROS) in CD4+ T (Th17) cells and Tc17 cells by glutathione depletion, resulting in IL-17 suppression particularly in Tc17 cells. Accordingly, IL-17 production by CD8+ but not by CD4+ T cells was reduced in DMF-treated MS patients and DMF application diminished Tc17 cell pathogenicity in EAE. Accumulated ROS shifts the Tc17 transcriptome towards a cytotoxic T lymphocyte (CTL)-like signature by enhancing IL-2 signalling including phosphoinositide-3-kinase (PI3K)/ protein kinase B (AKT) and signal transducer and activator of transcription (STAT)5 pathways. AKT deactivated forkhead-box-Protein O (FOXO)1 leading to the upregulation of the transcription factor T-box transcription factor TBX21 (T-bet), which in turn suppressed IL-17. The modified transcriptional network was accompanied by altered histone modifications at the Il17 locus. In line, T-bet-deficiency, inhibition of histone deacetylases (HDAC), PI3K/AKT or STAT5 partially prevented DMF-mediated suppression of Tc17 cells. Thus, this work provides mechanistic insights into the selective modulation of Tc17 cell differentiation by DMF-mediated upregulation of ROS and IL-2 signalling with relevance for Tc17-driven pathologies including MS and psoriasis

Cellular localization of the hybrid pyruvate/2-oxoglutarate dehydrogenase complex in the actinobacterium Corynebacteriumglutamicum

For many bacterial proteins, specific localizations within the cell have been demonstrated, but enzymes involved in central metabolism are usually considered to be homogenously distributed within the cytoplasm. Here, we provide an example for a spatially defined localization of a unique enzyme complex found in actinobacteria, the hybrid pyruvate/2-oxoglutarate dehydrogenase complex (PDH-ODH). In non-actinobacterial cells, PDH and ODH form separate multienzyme complexes of megadalton size composed of three different subunits, E1, E2, and E3. The actinobacterial PDH-ODH complex is composed of four subunits, AceE (E1p), AceF (E2p), Lpd (E3), and OdhA (E1oE2o). Using fluorescence microscopy, we observed that in Corynebacterium glutamicum, all four subunits are co-localized in distinct spots at the cell poles, and in larger cells, additional spots are present at mid-cell. These results further confirm the existence of the hybrid complex. The unphosporylated OdhI protein, which binds to OdhA and inhibits ODH activity, was co-localized with OdhA at the poles, whereas phosphorylated OdhI, which does not bind OdhA, was distributed in the entire cytoplasm. Isocitrate dehydrogenase and glutamate dehydrogenase, both metabolically linked to ODH, were evenly distributed in the cytoplasm. Based on the available structural data for individual PDH-ODH subunits, a novel supramolecular architecture of the hybrid complex differing from classical PDH and ODH complexes has to be postulated. Our results suggest that localization at the poles or at mid-cell is most likely caused by nucleoid exclusion and results in a spatially organized metabolism in actinobacteria, with consequences yet to be studied

Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages

Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein–coupled receptor–dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system