Human embryonic stem cells suppress T cell responses via arginase I-dependent mechanism.
Human embryonic stem cells (hESCs) can proliferate extensively in culture and give rise to progeny of the three germ layers. Several reports suggested that mouse and hESCs may attenuate immune responses. In this study, we focused on the mechanism by which hESCs inhibit T cell responses. Using coculture experiments, we demonstrate that hESCs inhibit cytokine secretion and T cell proliferation in response to potent T cell activators. Furthermore, we show that hESCs downmodulate the TCR-associated CD3-zeta chain. These effects are maintained when hESCs are replaced by their conditioned media and can be restored by the addition of L-arginine to hESC-conditioned media or by treatment of hESCs with a specific arginase inhibitor. Moreover, we show arginase-I expression and activity in hESCs. We further demonstrate that mouse ESCs (mESCs) similarly inhibit T cell activation via arginase I, suggesting an evolutionary conserved mechanism of T cell suppression by ESCs. In addition, we demonstrate that arginase I expression is not limited to ESCs in culture, but can also be detected in the inner cell mass and the trophectoderm of preimplantation mouse embryos and hESC-derived trophectoderm cells. Finally, T cells infiltrating ESC-derived teratomas have significantly lower levels of CD3-zeta chain. Collectively, the data indicate a role for ESC-arginase I activity in the attenuation of T cell activation.
Yachimovich-Cohen
Nurit
N
Hadassah Human Embryonic Stem Cell Research Center, Goldyne Savad Institute of Gene Therapy, Hadassah University Medical Center, Jerusalem, Israel.
Even-Ram
Sharona
S
Shufaro
Yoel
Y
Rachmilewitz
Jacob
J
Reubinoff
Benjamin
B
D000328:Adult; D000818:Animals; D001119:Arginase / Q000502:physiology*; D001120:Arginine / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000201:enzymology* / Q000276:immunology* / Q000637:transplantation; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D013724:Teratoma / Q000201:enzymology / Q000276:immunology / Q000473:pathology
D017252:CD3 Complex; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D001120:Arginine; D001119:Arginase