Immunomodulation of Embryonic Stem Cell-produced MFG-E8 on T Cells

Abstract

Embryonic stem cells (ESCs) possess certain immunomodulatory properties; the defined components in ESCs, however, are largely unknown. Based on proteomic database, I report here that milk fat globule epidermal growth factor 8 (MFG-E8) is a key component in ESCs to suppress T cell activation and regulate T cell polarization. MFG-E8 is enriched in undifferentiated ESCs while diminishing in differentiated ESCs. Neutralizing ESC-derived MFG-E8 substantially ameliorates the suppressive effects of ESCs on T cell activation and proliferation. Additionally, MFG-E8 in ESCs is capable of up-regulating T regulatory cells. I further prove that MFG-E8 suppresses T cell activation and regulates T cell polarization through inhibiting PKCθ phosphorylation. In vivo teratoma formation assay reveals an increase in ESC engraftments across allogeneic barriers with less immunologic rejection by up-regulation of MFG-E8 expression in ESCs, further validating the immunosuppressive properties of MFG-E8. Identifying an important immunoregulatory component in ESCs will greatly facilitate stem cell-based therapies.