title: MFG-E8 Is Critical for Embryonic Stem Cell-Mediated T Cell Immunomodulation.
abstract: The molecules and mechanisms pertinent to the low immunogenicity of undifferentiated embryonic stem cells (ESCs) remain poorly understood. Here, we provide evidence that milk fat globule epidermal growth factor 8 (MFG-E8) is a vital mediator in this phenomenon and directly suppresses T cell immune responses. MFG-E8 is enriched in undifferentiated ESCs but diminished in differentiated ESCs. Upregulation of MFG-E8 in ESCs increases the successful engraftment of both undifferentiated and differentiated ESCs across major histocompatibility complex barriers. MFG-E8 suppresses T cell activation/proliferation and inhibits Th1, Th2, and Th17 subpopulations while increasing regulatory T cell subsets. Neutralizing MFG-E8 substantially abrogates these effects, whereas addition of recombinant MFG-E8 to differentiated ESCs restores immunosuppression. Furthermore, we provide the evidence that MFG-E8 suppresses T cell activation and regulates T cell polarization by inhibiting PKCθ phosphorylation through the α3/5βV integrin receptor. Our findings offer an approach to facilitate transplantation acceptance.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Bodour
authors.initials: B
authors.lastname: AlKhamees
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Deyong
authors.initials: D
authors.lastname: Jia
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Couture
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Figeys
authors.affiliation: Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjiku-ku, Tokyo 160-8582, Japan. Electronic address: jinushi@z7.keio.jp.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Jinushi
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Electronic address: lwang@uottawa.ca.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D006648:Histocompatibility; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D000954:Antigens, Surface; C490919:Mfge8 protein, mouse; D008894:Milk Proteins