Aim: To obtain promising immunosuppressants from endophytic fungus. Methods and Results:The endophytic fungus Mycosphaerella nawae (ZJLQ129) was isolated from the plant Smilax china L. and its secondary metabolites extracted and fractionated through column chromatography. The metabolites were further modified by a derivatization reaction with ammonium hydroxide. After isolation and derivatization, a new dibenzofuran named as (+)isomycousnine enamine (iME) was obtained. The structures of the derivatives were determined based on chemical evidences and extensive spectroscopic methods including 2D-NMR, DEPT and HRESI-MS spectra. The immune activities of iME were first evaluated on the proliferation and cytokines (IL-2 and IFN-γ) production of T and B cells by using MTT and ELISA methods respectively. Then, its effects on the proliferation of T-cell subsets (CD4 + and CD8 + T cells), as well as CD25 and CD69 expressions were also determined by flow cytometry. Finally, by using Cytometric Bead Array (CBA), the impacts of iME on the secretion of Th1/Th2/Th17 cytokines from purified CD4 + T cells were assayed. The results showed that iME not only selectively suppressed the immune responses of T cells, but also preferentially inhibited the activation and proliferation of CD4 + T cells. Conclusion: A novel dibenzofuran derived from endophytic fungus Mycosphaerella nawae preferentially inhibits CD4 + T-cell activation and proliferation. Significance and Impact of the Study: This work obtained iME, a new dibenzofuran derived from endophytic fungus. iME has the capacity to inhibit CD4 + T-cell activation and therefore is a novel potential immunosuppressant for development in the future.