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Immunol."],"abstract":"<jats:p>Recent reports have shown the importance of IFN-\u03b3 and T-bet<jats:sup>+<\/jats:sup> B cells in the pathology of SLE, suggesting the involvement of IFN-\u03b3-producing T-bet<jats:sup>+<\/jats:sup> CD4<jats:sup>+<\/jats:sup> cells, i.e., Th1 cells. This study determined the changes in Th1 subsets with metabolic shift and their potential as therapeutic targets in SLE. Compared with healthy donors, patients with SLE had higher numbers of T-bet<jats:sup>hi<\/jats:sup>CXCR3<jats:sup>lo<\/jats:sup> effector cells and T-bet<jats:sup>+<\/jats:sup>Foxp3<jats:sup>lo<\/jats:sup> non-suppressive cells, which excessively produce IFN-\u03b3, and lower number of non-IFN-\u03b3-producing T-bet<jats:sup>+<\/jats:sup>Foxp3<jats:sup>hi<\/jats:sup> activated-T<jats:sub>reg<\/jats:sub> cells. These changes were considered to be involved in treatment resistance. The differentiation mechanism of Th1 subsets was investigated <jats:italic>in vitro<\/jats:italic> using memory CD4<jats:sup>+<\/jats:sup> cells obtained from healthy donors and patients with SLE. In memory CD4<jats:sup>+<\/jats:sup> cells of healthy donors, both rapamycin and 2-deoxy-D-glucose (2DG) suppressed T-bet<jats:sup>+<\/jats:sup>Foxp3<jats:sup>-<\/jats:sup> cells, and induced T-bet<jats:sup>+<\/jats:sup>Foxp3<jats:sup>+(lo\/hi)<\/jats:sup> cells. Rapamycin induced IFN-\u03b3-producing T-bet<jats:sup>+<\/jats:sup>Foxp3<jats:sup>lo<\/jats:sup> cells accompanied with enhanced lipid metabolism, whereas 2DG induced IFN-\u03b3-non-producing T-bet<jats:sup>+<\/jats:sup>Foxp3<jats:sup>hi<\/jats:sup> cells. In memory CD4<jats:sup>+<\/jats:sup> cells of SLE patients, inhibition of fatty acid synthesis, but not \u03b2-oxidation, suppressed IFN-\u03b3 production, and up-regulated of Foxp3 expression in T-bet<jats:sup>+<\/jats:sup>Foxp3<jats:sup>+<\/jats:sup> cells. Metabolic regulators such as fatty acid synthesis inhibitors may improve the pathological status by correcting Th1 subset imbalance and overproduction of IFN-\u03b3 in SLE.<\/jats:p>","DOI":"10.3389\/fimmu.2020.593103","type":"journal-article","created":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T06:29:27Z","timestamp":1606717767000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-\u03b3 Overproduction in T Helper 1 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