Human Embryonic Stem Cells Suppress T Cell Responses via Arginase I-Dependent Mechanism

Abstract

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-ζ 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-ζ chain. Collectively, the data indicate a role for ESC-arginase I activity in the attenuation of T cell activation.

Immunogenicity of human embryonic stem cell-derived beta cells

“…This suggests that hESC-PEs do not employ active suppression of CTL responses, as has been observed in other studies [21]. Further, HLA expression could be induced by mimicking inflammation with IFNγ.…”

“…Low expression of HLA by hESCs and hESC-derived cells underlies the hypoimmunogenicity observed in most published studies, effectively hiding cells from T cell recognition and alloreactive antibodies, while differentiation can upregulate HLA and increase vulnerability to immunity [17][18][19][20][21]. In our study, immunogenicity to alloreactive and peptide (CMV)-specific responses was related to HLA expression.…”

“…Preproinsulin (PPI)-specific T cell clone 1E6 generation was described previously [23]. Briefly, PBMCs from an individual with type 1 diabetes were stimulated with PPI [15][16][17][18][19][20][21][22][23][24] peptide. PPI-specific cytotoxic T lymphocytes (CTLs) were sorted by FACS and expanded.…”

“…However, differentiation of hESCs to other cell types can result in the loss of this immunological privilege [17][18][19][20][21]. Insights into the immunogenicity of the alternative sources of beta cells can help to guide the choice of immune-protective strategies and the relevant immune monitoring to be employed in clinical introduction.…”

Human Embryonic Stem Cell-extracts Inhibit the Differentiation and Function of Monocyte-derived Dendritic Cells

“…Moreover, we recently reviewed a list of highly abundant proteins found in hESCs using quantitative mass spectrometry and have not found any known candidate factors such as CTLA-4, PDL-1, PDL-2, and HLA-G (unpublished observations). A recent publication has implicated arginase-1 as a possible mechanism for hESCs mediated T cell suppression [45]. In our experiments the vehicle/lysis buffer is supplemented with 50 mM Larginine as this has been found to enhance protein stability and prevent dimer formation [46,47].…”