TNFR2 signals promote serine metabolism to preserve Regulatory T cell function by regulating SLC7A10 2254289

Introduction TNFR2 is primarily expressed by CD4+Foxp3+ regulatory T (Treg) cells, which are crucial in maintaining immune homeostasis and preventing autoimmunity, Amino acid metabolism plays an important role in maintaining the activity and function of Treg cells. However, the molecular mechanism by which TNFR2 signaling regulates Treg cells by influencing cellular amino acid metabolism remains unclear. Methods WT and TNFR2-deficient Treg cells were purified by FACS sorting analysis, then RNA-bulk Seq was performed to examine the differential expressed genes. RT-qPCR, and flow cytometry were conducted to validate the potential genes that are targeted by TNFR2. Limitation of cellular Serine in vitro and in vivo were applied to reveal the change of Treg cell proliferation and function. Results In this study, we found that SLC7A10 was a significant upregulated gene in Tregs by TNFR2 signaling. Silence of SLC7A10 decreased the proportion of Treg cells and their expression of CTLA4, PD-1, and consequently inhibited its proliferation and suppressive function. Since SLC7A10 is one of the representative neutral amino acid transporter genes, especially serine transportation. We further confirmed that knockdown of SLC7A10 reduced the uptake of serine in Treg cells, in consistent, the limitation of serine in vitro significantly suppressed the proliferation and suppressive function of Treg cells. Therefore, SLC7A10, upregulated in TNF-TNFR2 signaling, plays critical role in maintaining the serine metabolism of Treg cells. Conclusion Our study for the first time found that TNFR2 promotes serine metabolism by regulating SLC7A10 in Treg cells. The findings suggest that SLC7A10 is not only expressed by Tregs but also exerts specific functions for maintaining Treg activation.