...to chronic deletion of Goti, tamoxifen-induced acute Goti deletion resulted in a robust reduction in IL-17 and a reciprocal increase in FOXP3 in TH17 cell cultures (Fig. 1j). ...when subjected to EAE induction, tamoxifen-treated Gotr/flCd4-creERT2 mice showed a decreased ratio of IL-17+ cells but an increased ratio of FOXP3+ T cells infiltrated in the central nervous system, as well as a significantly reduced EAE disease score (Fig. 1a-i). A cellular study also demonstrated that GOT1 can operate in both flux directions8. ...presuming a locked-in, specific directionality for GOT1 in differentiating T cells is misguided. Both the total abundance of aKG and the abundance ofU-13CaKG (representing newly synthesized aKG from glutamine or glutamate) are decreased by more than 60% (from W. Xu et al.2, data not shown). ...one can infer that the activity of GOT1 mediates the glutamate-to-aKG conversion, with the changes in labelled metabolite abundance supporting a directionality during TH17 cell differentiation that is opposite to what W. Xu et al.2 proposed. The context of their study2 is therefore different to that of our original study1 regarding the role of the enzymatic function of GOT1 (in a therapeutically more-relevant context-that is, acute deletion or inhibition) in TH17 cell differentiation. ...small-molecule inhibitors or acute or chronic deletion of a particular gene may result in a very different phenotype because of the multifunctionality of proteins and compensatory effects3,4.