Most of current immunosuppressive agents have severe side effects due to their non-selective effect patterns.Here we report a series of natural products that show a selective inhibition on T cell-mediated immune response distinct from current drugs.These small molecule compounds include a new cerebroside fusaruside, a plant cyclopeptide astin C, plant flavonoids Jaceosidin, cirsilineol and astilbin, and the fungal metabolites fumigaclavine C and its derivatives, etc.Among them, astin C induces apoptosis of activated T cells with a mitochondria-dependent but not endoplasmic reticulum stress-mediated pathway.Jaceosidin and cirsilineol exert their immunosuppressive effects through downregulation of the IFN-γ/STAT1/T-bet signaling in T cells.As to fusaruside, this unique compound triggered tyrosine phosphorylation of Src homology 2-containing protein tyrosine phosphatase 2 (SHP-2) in T cells from C57BL/6 mice.Then the interaction of pY-SHP-2 with cytosolic STAT1 stopped the recruitment of STAT1 to IFN-γreceptor for phosphorylation and selectively inhibited STAT1 signaling, which led to a reduction in Thl cytokine levels and an improvement of experimental colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) in mice.Blocking the pY-SHP-2-STAT1 interaction, by using either the SHP-2 inhibitor NSC-87877 or shp-2-/-T cells, prevented the inhibition of STAT1 activation and abolished the improvement of colitis by fusaruside.All above compounds are valuable to be further investigated on the detailed mechanisms and the possibility as a novel drug candidate for a variety of immune diseases.