Cell-based high throughput screening identified a novel compound that promotes regulatory T cells and prevents autoimmune colitis

Abstract

Regulatory T cells (T_R) show great promise for treating autoimmune diseases, allergies and preventing transplant rejection; however, their clinical application has been hampered by the lack of efficient ex vivo or in vivo expansion strategies. Here we report screening data on 130,000 low molecular weight (LMW) compounds for their T_R promoting potential using a self-developed high-throughput cell-based assay. One of the lead compounds, an isoxazolecarboxamide designated as TRP38, efficiently converts naïve CD4⁺ T cells to T_R cells in vitro and protects mice from autoimmune colitis in vivo. In addition, TRP38 can synergize with other compounds and/or cytokines such as rapamycin and TGFβ for T_R conversion, probably via directly inhibiting P70s6 phosphorylation without affecting mTOR expression, underscoring the importance of complementary and coordinated activity of multiple signaling pathways for the increased level of stable T_R cell production.