Kurzfassung

Upon activation, during adaptive immune responses, CD4+ T cells undergo a drastic metabolic reprogramming in order to orchestrate and fuel proliferation and differentiation. Due to this higher energetic and biosynthetic precursor demand, effector T cells require an increased glycolytic-lipogenic rate. To achieve this, activated cells upregulate the expression of glycolysis and glutaminolysis-associated genes, including nutrient transporters. As a result, highly proliferating cells gain a...Upon activation, during adaptive immune responses, CD4+ T cells undergo a drastic metabolic reprogramming in order to orchestrate and fuel proliferation and differentiation. Due to this higher energetic and biosynthetic precursor demand, effector T cells require an increased glycolytic-lipogenic rate. To achieve this, activated cells upregulate the expression of glycolysis and glutaminolysis-associated genes, including nutrient transporters. As a result, highly proliferating cells gain a source of rapid ATP (via aerobic glycolysis) and, on the other hand, are readily provided with precursors for protein, nucleotide and lipid synthesis, and the signaling required for the effector T cell function. We could demonstrate recently the importance of de novo fatty acid synthesis (FAS) during T cell activation. We proposed that inhibiting this pathway with a natural compound (Soraphen A, SorA) derived from myxobacteria could potentially be used to inhibit the differentiation of effector T (Teff) cells while at the same time inducing regulatory T (Treg) cells as a therapy in human autoimmune disease. In addition, mitochondrial respiration via oxidative phosphorylation (OXPHOS) has been found to be an essential driver of T cell activation. We discovered that blocking mitochondrial translation in vitro with another myxobacteria-derived natural compound (Argyrin C, ArgC) strongly downregulates cytokine production by T helper (Th)1, Th2 and Th17 cells. We postulate here that interfering with translation of mitochondrial-encoded electron transfer chain (ETC) subunits limits oxygen consumption during differentiation, progressively compromising the metabolic cues needed for effector T cell differentiation and proliferation. In addition to effectively blocking the course of a CD4+ T cell-mediated autoimmune disease (experimental autoimmune encephalomyelitis, EAE), our data suggest that this pathway can also be modulated to ameliorate symptoms in the mouse model of imiquimod (IMQ)-induced psoriasis. In summary, our results indicate that targeting FAS or the mitochondrial translation machinery limits effector T cell function, thereby providing novel strategies to treat inflammatory skin diseases. We propose to study the therapeutic potential of SorA and ArgC (and related molecules) in a mouse model of psoriasis and we plan to unveil the molecular mechanism of ArgC by the use of novel genetic models with conditional ablation of putative target molecules of ArgC.» weiterlesen» einklappen