CD46 is not only identified as a complement regulatory protein which protects host cells from complement attack,but also a new co-stimulatory molecule for human T cells.CD3/CD46 co-stimulation can induce a T-regulatory 1 cell(Tr1)-specific cytokine phenotype in human CD4+T cells.However,the role of CD46 as a co-stimulatory molecule in the modulation of the acquired immunity,such as transplant immunology,remains unclear.In this study,CD4+T cells were isolated from human CD46-transgenic C57BL/6 mice by magnetic-activated cell sorting,and further induced by anti-CD3,anti-CD28 and anti-CD46 antibodies respectively,and anti-CD3/anti-CD28 antibodies,anti-CD3/anti-CD46 antibodies,or the monoclonal antibody panel against CD3/CD28/CD46.The levels of interleukin-2(IL-2),γ-interferon(γ-IFN),interleukin-10(IL-10)and transforming growth factor-β(TGF-β)were detected in the supematants of different groups.Suppression of allogeneic T cell proliferation were assessed by using mixed lymphocyte reaction(MLR)assay,in which monoclonal antibodies against CD46 were added to the culture.The results showed that CD3/CD28,CD3/CD46 and CD3/CD28/CD46 co-stimulation could significantly induce stronger proliferation of T cells than CD3 stimulation(P＜0.05),and CD3/CD28/CD46 co-stimulation significantly increased the proliferation of T cells when compared with CD3/CD28 or CD3/CD46 co-stimulation(P＜0.05 for each).IL-2 and γ-IFN levels were much higher in CD3/CD28 co-stimulation group than in CD3,CD28,CD46 and CD3/CD46 groups(P＜0.05 for each).IL-10 and TGF-β levels were dramatically increased in CD3/CD46 co-stimulation group as compared with those in the CD3,CD28,CD46 and CD3/CD28 groups(P＜0.05 for each).CD3/CD46 co-stimulation significantly inhibited the T cell proliferation and allogenic immune responses through the secretion of IL-10 and TGF-β in MLR (P＜0.05).These results suggested that CD3/CD46 can induce Tr1 cells to modulate allogenic immune responses,and it may become a novel target for the development of new therapeutic approach for T-cell-mediated diseases.CD46 plays an important role in regulating the T cell-mediated immune responses by bridging innate and acquired immunity.