Reprogramming of the MHC-I and Its Regulation by NF[kappa]B in Human-Induced Pluripotent Stem Cells

The immunogenicity of human pluripotent stem cells plays a major role in their potential use in the clinic. We show that, during their reprogramming, human-induced pluripotent stem (iPS) cells downregulate expression of human leukocyte antigen (HLA)-A/B/C and [beta]2 microglobulin ([beta]2M), the two components of major histocompatibility complex-I (MHC-I). MHC-I expression in iPS cells can be restored by differentiation or treatment with interferon-gamma (IFN[gamma]). To analyze the molecular mechanisms that regulate the expression of the MHC-I molecules in human iPS cells, we searched for correlation between the expression of HLA-A/B/C and [beta]2M and the expression of transcription factors that bind to the promoter of these genes. Our results show a significant positive correlation between MHC-I expression and expression of the nuclear factors, nuclear factor kappa B 1 (NF[kappa]B1) and RelA, at the levels of RNA, protein and was confirmed by chromatin binding. Concordantly, we detected robust levels of NF[kappa]B1 and RelA proteins in the nucleus of somatic cells but not in the iPS cell derived from them. Overexpression of NF[kappa]B1 and RelA in undifferentiated pluripotent stem cells led to induction in expression of MHC-I, whereas silencing NF[kappa]B1 and RelA by small hairpin RNA decreased the expression of [beta]2M after IFN[gamma] treatment. Our data point to the critical role of NF[kappa]B proteins in regulating the MHC-I expression in human pluripotent stem cells. STEM CELLS 2012;30:2700-2708 [PUBLICATION ABSTRACT]