Small organic molecules accelerate the expansion of regulatory T cells

The regulatory T cells (T_reg cells) expressing CD4 + CD25 + FOXP3 + markers are indispensable for the initiation of immune homeostasis and tolerance to self-antigens in both mice and humans. A decrease in regulatory T cells leads to various autoimmune pathologies. Herein, we report three low molecular weight, small organic molecules as a new series of T_reg proliferators TRP-1-3. These small molecules were tested for their proliferative effect on regulatory T cells. It was found that TRP-1 (Oleracein E) strongly accelerates the T_reg proliferation in vitro in a concentration-dependent manner. The effect was evident for all subsets of T_reg cells tested, including naturally occurring, thymus-derived and peripherally-induced or adaptive T_reg, indicating an effect independent of the maturation site. Importantly, increased T_reg cells numbers by TRP-1 correlated with improved CD4 + CD25 + FOXP3 + expression in vitro, while propidium iodide-based staining showed low TRP-1-induced cytotoxicity. Molecular docking plus simulation studies of these TRP-1-3 with IL-2R, mTOR and TCR receptors suggest a TCR-based T_reg cells activation mechanism. Because of its high T_reg cells activities and low cellular cytotoxicity, TRP-1-3 may be useful in stimulating ex-vivo/in-vivo, T_reg cell-specific responses for therapeutic applications.