It is well known that brain-derived neurotrophic factor (BDNF) is a one of neurotrophic factors and a key player in brain, however, there are few reports whether BDNF affects immune cells. In this study, we show the BDNF production in HTLV-1 infected cell lines, MT-2 and HUT102. Western blotting shows BDNF-specific receptor, TrkB expressions on MT-2 and HUT102 cells. Furthermore, anti-BDNF antibody partially blocked the proliferation of MT-2 and HUT102 cells at 24 h and 48 h. These results suggest that autocrine loop of BDNF may take part in the proliferation of leukemia cells. Next we set and investigate BDNF effects on splenocytes in murine system. Western blotting showed splenocytes and macrophages expressed TrkB. The proliferation of splenocytes induced by mitogen was inhibited in the presence of BDNF. Interestingly, western blotting demonstrated that BDNF induced FOXP3 expression in murine CD4 positive T cells, which was inhibited by specific inhibitor for NF-AT and RhoA. Reporter assay demonstrated that BDNF activated AP1 and NF-AT reporter. These results suggest that BDNF induced Foxp3 through JNK-AP1 pathway and NF-AT, and suppressed immune response. Finally, we investigated whether BDNF has effects in vivo. At 24 h after the BDNF administration by i.n., splenocytes and bone marrow cells were prepared. Splenocyte proliferation stimulated by mitogen was attenuated in BDNF-treated mice. Additionally, TNF-α production induced by LPS was lower than that of control mouse in bone-marrow derived macrophages. These results suggested that BDNF contributes immune suppressive event in vivo. Taken together, BDNF plays an important role on immune responses by attenuating cytokines and induction of regulatory T cells.