title: Suppression of allogeneic T cells proliferation by CD3/CD46-induced T-regulatory 1 cells.
abstract: 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), gamma-interferon (gamma-IFN), interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) were detected in the supernatants 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 gamma-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-beta 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-beta 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.
authors.affiliation: Institute of Organ Transplantation, Department of General Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. dchen@tjh.tjmu.edu.cn
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Zhishui
authors.initials: Z
authors.lastname: Chen
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.forename: Weijie
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D051916:Membrane Cofactor Protein / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*
chemical_list: D017252:CD3 Complex; D051916:Membrane Cofactor Protein