Preliminary Screening Of The Effects Of FASN-mediated Fatty Acid Synthesis Metabolism On The Differentiation And Function Of Various Subsets Of CD4~+ T Cells

De novo fatty acid synthesis is an important process of cell synthesis and metabolism.In this process,the carbon source derived from the oxidation of glucose or other biological macromolecules is transported to palmitate and saturated long-chain fatty acid(LCFA),and the saturated LCFA can be further modified to form more complex lipids.Fatty acid synthase(FASN)and acetyl-Co A carboxylase 1(ACC1)are the key enzymes in this process.FASN mediates the final process of condensation of palmitate by acetyl-Co A and malonyl-Co A.Previous studies have shown that fatty acid synthesis mediated by ACC1 plays an important role in the proliferation and differentiation of Th17cells.But the role of FASN-mediated fatty acid synthesis on the differentiation of CD4~+T cell subsets is still largely unknown.To address this scientific question,we first analyzed the FASN protein content in various T cell subsets differentiated in vitro,and found that FASN was abundant in Th0,Th2 and Th17 cells,weakly expressed in Th1 cells,while barely detectable in Th9 or Treg cells.These findings suggest that FASN might play divergent roles in different T cell subsets.To test this hypothesis,we constructed Fasn-flox/flox mice and hybridized with CD4-cre to obtain T cell specific FASN deficient mice.Na?ve CD4~+T cells were sorted from these mice and used for in vitro differentiation.Indeed,FASN deficiency hindered the differentiation of Th17,which was consistent with previous reports showing similar findings using ACC1-KO cells.However,FASN was dispensable for the differentiation of Treg cells,the in vitro and in vivo suppressive function of Treg cells were not affected by the deficiency of FASN either.Consistent with the expressing levels of FASN in Th1 and Th2 cells,FASN deficiency slightly inhibited the differentiation of Th1 cells,but significantly reduced IL-4 expression in Th2 cells.In the mouse asthma model induced by ovalbumin,we found that Th2 cells-mediated type 2 immune response was also suppressed in CD4-cre Fasn-flox/flox mice,the content of OVA-specific Abs in the serum and the number of alveolar infiltrating immune cells were decreased in the KO group.Collectively,these results reveal that FASN is an important metabolic checkpoint in the differentiation of Th2 and Th17 subsets,but does not affect the differentiation and immunosuppressive function of Treg cells.These findings expand our understanding of fatty acid metabolism in T cells and provide guidance for further investigation.