Immunumometabolic role of sterol element binding protein 1C (SREBP1C) in Tregulatory cell function

Background and Aims : Cellular metabolism defines T cell polarization and activation; Tregulatory (Treg) cells rely on fatty acids oxidation (FAO) for their suppressive function while glycolysis is preferred for cell migration. We aimed at studying how SREBP1c, a key protein regulating intracellular fatty acid (FA) metabolism, impacts Treg cell metabolism and function.Methods: A detailed immunophenotyping through flow cytometry and metabolic profiling of isolated Tregulatory (CD4+CD25+) and in vitro induced Treg (iTreg) cells were performed together with in vitro and in vivo assays of Treg function from SREBP1c KO and WT littermates.Results: Srebp1c KO mice presented reduced circulating and tissues’ level of Treg compared to WT mice (-66%,p<0,01). Functionally, Srebp1c deficiency was associated with a reduced suppressive (-21%,p<0,01) and increased migratory function (+40%,p<0,05). In Experimental Autoimmune Encephalomyelitis, a model of immune challenge, Treg from KO mice were less effective compared to WT in limiting disease progression. Taking advantage from iTreg we confirmed that the less suppressive and more migratory phenotype was the consequence of Srebp1c deficiency in Treg rather than an effect of reduced cholesterol and triglycerides plasma levels in KO vs WT (-56%,-61%,p<0.01). Metabolically, KO iTreg showed an increased glycolytic potential with preserved mitochondrial function. Accumulation of lactate (+20%,p<0,01) and increased mTORC1 activation by pS6 phosphorylation (+45%,p<0,01) further confirmed a switch to anaerobic glycolysis in KO Treg.Conclusions: SREBP1c represents a key player of Treg immunometabolism by controlling glycolysis and cell migration. Metabolic fluxes are ongoing to depict the molecular mechanism/s of this phenotype. Background and Aims : Cellular metabolism defines T cell polarization and activation; Tregulatory (Treg) cells rely on fatty acids oxidation (FAO) for their suppressive function while glycolysis is preferred for cell migration. We aimed at studying how SREBP1c, a key protein regulating intracellular fatty acid (FA) metabolism, impacts Treg cell metabolism and function. Methods: A detailed immunophenotyping through flow cytometry and metabolic profiling of isolated Tregulatory (CD4+CD25+) and in vitro induced Treg (iTreg) cells were performed together with in vitro and in vivo assays of Treg function from SREBP1c KO and WT littermates. Results: Srebp1c KO mice presented reduced circulating and tissues’ level of Treg compared to WT mice (-66%,p<0,01). Functionally, Srebp1c deficiency was associated with a reduced suppressive (-21%,p<0,01) and increased migratory function (+40%,p<0,05). In Experimental Autoimmune Encephalomyelitis, a model of immune challenge, Treg from KO mice were less effective compared to WT in limiting disease progression. Taking advantage from iTreg we confirmed that the less suppressive and more migratory phenotype was the consequence of Srebp1c deficiency in Treg rather than an effect of reduced cholesterol and triglycerides plasma levels in KO vs WT (-56%,-61%,p<0.01). Metabolically, KO iTreg showed an increased glycolytic potential with preserved mitochondrial function. Accumulation of lactate (+20%,p<0,01) and increased mTORC1 activation by pS6 phosphorylation (+45%,p<0,01) further confirmed a switch to anaerobic glycolysis in KO Treg. Conclusions: SREBP1c represents a key player of Treg immunometabolism by controlling glycolysis and cell migration. Metabolic fluxes are ongoing to depict the molecular mechanism/s of this phenotype.