Characteristic Expression of Major Histocompatibility Complex and Immune Privilege Genes in Human Pluripotent Stem Cells and Their Derivatives

Abstract

Pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), have been regarded as useful sources for cell-based transplantation therapy. However, immunogenicity of the cells remains the major determinant for successful clinical application. We report the examination of several hESC lines (NTU1 and H9), hiPSC lines, and their derivatives (including stem cell-derived hepatocytes) for the expression of major histocompatibility complex (MHC), natural killer (NK) cell receptor (NKp30, NKp44, NKp46) ligand, immune-related genes, human leukocyte antigen (HLA) haplotyping, and the effects in functional mixed lymphocyte reaction (MLR). Flow cytometry showed lower levels (percentages and fluorescence intensities) of MHC class I (MHC-I) molecules, b2-microglobulin, and HLA-E in undifferentiated stem cells. The levels were increased after cotreatment with interferon-g and/or in vitro differentiation. Antigen-presenting cell markers (CD11c, CD80, and CD86) and MHC-II (HLA-DP, -DQ, and -DR) remained low throughout the treatments. Recognition of stem cells/derivatives by NK lysis receptors were lower or absent. Activation of responder lymphocytes was significantly lower by undifferentiated stem cells than by allogeneic lymphocytes in MLR, but differentiated NTU1 hESCs induced a cell number-dependent lymphocyte proliferation comparable with that by allogeneic lymphocytes. Interestingly, activation of lymphocytes by differentiated hiPSCs or H9 cells became blunted at higher cell numbers. Real-time reverse transcriptase PCR (RT-PCR) showed significant differential expression of immune privilege genes Arginase 2, Indole 1, GATA3, POMC, VIP, CALCA, CALCB, CD95L, CR1L, Serpine 1, HMOX1, IL6, LGALS3, HEBP1, THBS1, CD59, and LGALS1) in pluripotent stem cells/derivatives when compared to somatic cells. It was concluded that pluripotent stem cells/derivatives are predicted to be immunogenic, though evidence suggests some level of potential immune privilege. In addition, differential immunogenicity may exist between different pluripotent stem cell lines and their derivatives.

Human induced pluripotent stem cell–derived neurons improve motor asymmetry in a 6-hydroxydopamine–induced rat model of Parkinson's disease

“…iPS cells overcome the immunerejection and ethical issues related to the hES cells and fetal brainederived cells and would provide a wide application of cell-based therapy for neurodegenerative diseases, including PD [34,35]. Mouse iPS cellederived neural precursor cells were shown to migrate to brain regions and differentiated into neurons and glia, playing functions in improving the motor defects of rat PD models when injected into the brains of PD rats [24].…”

Induced Pluripotent Stem Cells have Similar Immunogenic and More Potent Immunomodulatory Properties Compared with Bone Marrow-Derived Stromal Cells in Vitro

“…Investigation into the immunogenic properties and immune plasticity of iPSCs has just recently begun [7,12,44–47]. It is known that undifferentiated iPSCs, like ESCs, express low or absent levels of MHC class I, and are negative for MHC class II expression [47,48].…”

“…It is known that undifferentiated iPSCs, like ESCs, express low or absent levels of MHC class I, and are negative for MHC class II expression [47,48]. Unlike MSCs, iPSC MHC class II expression is not upregulated by differentiation or by stimulation with IFN-γ [47–50]. The extent to which MHC class I expression can change upon iPSC differentiation or stimulation with proinflammatory cytokines, however, is not understood.…”

Immunobiology of HLA Class-Ib Molecules in Transplantation

“…Therefore, it is still debatable whether HLA-Ib alleles should be matched for all transplants, and if so, whether the immunosuppressive function of HLA-Ib molecules is mediated by the donor's molecules or those of the recipient. Some studies emphasize that the allograft (donor cells) should be expressing HLA-Ib molecules-and at high levels-in order to evade the cytotoxic activity of NK cells and CD8+ T cells that lead to graft rejection [18,[87][88][89] because cell-to-cell contact is mandatory for the interaction of HLA-Ib molecules and their inhibitory receptors to prevent the lysis of allograft cells by NK cells and CD8+ T cells [90]. Promoting the expression of HLAIb-rather than sHLA-Ib-by the donor's cells therefore provides the best and most specific strategy for helping allograft cells evade cell-mediated damage (or rejection).…”