Mammalian expression cloning of two human trophoblast suppressors of majorhistocompatibility complex genes

PROBLEM: Human trophoblasts suppress interferon-gamma (IFN-gamma)-simulated expression of major histocompatibility complex (MHC) class II genes and th ereby protect the conceptus from maternal immune attack. The mechanism of t his suppression is poorly understood. METHOD OF STUDY: IFN-gamma -responsive HeLa cells were stably transfected w ith trophoblast cDNA expression libraries and screened by negative immunose lection with an antibody to HLA-DR. RESULTS: Two suppressor cDNAs were isolated. One encoded the untranslated R NA. trophoblast STAT utron (TSU), which blocked STAT1 nuclear translocation and can theoretically form tripler RNA-DNA at the class II transactivator gene promoters. The other encoded the N-terminal 28 residues of chorionic s omatomammotropin (hCS). TSU-related genes were detected in human and macaqu e, but not in mouse, genomic DNA. CONCLUSIONS: The genetics of two human trophoblast MHC suppressors suggest that these functions have been gained in human placenta in recent evolution ary history. TSU and hCS play critical roles in suppression of MHC genes, w hich may lead to silencing by DNA methylation.