Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation

Experimental bacterial dysbiosis with consequent immune alterations increase intrarectal SIV acquisition susceptibility

“…Among the pathways differentially expressed longitudinally, differential regulation of cytokine production in intestinal epithelial cells by IL-17A and IL-17F was upregulated, as was differential regulation of cytokine production in macrophages and T helper cells by IL-17A and IL-17F ( Figure 2E ), with the epithelial-specific pathway additionally identified in our cross-section analysis ( Figure S2F ). To further explore Vanc-associated effects on host antimicrobial responsiveness, we measured expression of the pro-inflammatory bacterial sensors DUOX1/2 29 , 30 and SUCNR1 31 , 32 in rectal homogenates of post-treatment animals. By qRT-PCR, homogenates from Vanc animals exhibited increased expression (lower dCt) of DUOX2 and SUCNR1 compared with controls ( Figure 2F ).…”

“…Metabolites produced by the intestinal commensal microbiome control both local and systemic immunity. 49 Whereas metabolites such as SCFAs and riboflavin foster beneficial immunity, 22 , 50 pathobiont-derived uracil 29 , 51 and succinate 31 , 32 , 52 promote intestinal inflammation through DUOX2 and SUCNR1, respectively. Unrestrained DUOX2 signaling such as in the case of bacterial dysbiosis 29 , 51 or IL-22 deficiency 30 triggers intestinal inflammation and increases microbial translocation.…”

“…Unrestrained DUOX2 signaling such as in the case of bacterial dysbiosis 29 , 51 or IL-22 deficiency 30 triggers intestinal inflammation and increases microbial translocation. SUCNR1 signaling in response to luminal succinate calibrates the pro-inflammatory potential of intestinal macrophages and T cells, 31 , 32 with IL-22 shown to regulate succinate bioavail-ability. 52 Although an association between rectal HIV acquisition and availability of specific metabolites has not been formally explored, Chen et al demonstrated that among MSM, individuals that seroconvert have a distinct microbiome profile in the months prior to conversion compared with non-converters, suggestive of differential metabolomes.…”

Salmonellacancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity

“…To measure extracellular acidification (ECAR) and oxygen consumption rate (OCR), splenocytes (2 x 10 6 /well) were activated in technical triplicate from each mouse for 48h in TCM from non-treated or STm-infected tumour organoids. Cells were then washed and resuspended in “Seahorse XF” serum-free RPMI (Agilent), seeded onto pre-coated (poly-d-lysine; Invitrogen) Seahorse plates and analysed on a Seahorse XFe96 metabolic extracellular flux analyser as previously described (Gudgeon et al, 2022). Glucose (10mM Sigma) was first added and then Oligomycin (1 μM; Merck), BAM-15 (3 μM; Merck), rotenone (2 μM; Merck) and antimycin A (2 μM; Merck) were injected to disrupt various elements of the metabolic pathways.…”

The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy

“…While the effects of succinate accumulation on innate immune cell activity have been investigated, few studies have explored the role of succinate in modulating T-cell activity within the TME. A key study interrogating this relationship showed that high succinate levels in the TME can inhibit CD4+ and CD8+ T-cell effector function, particularly by blunting cytokine secretion (IFN-γ) and degranulation ( 195 ). Mechanistically, increased succinate uptake was found to inhibit T-cell succinyl-CoA synthetase activity, glycolytic flux, and the TCA cycle.…”