Repression of Major Histocompatibility Complex Genes by a Human Trophoblast Ribonucleic Acid

Abstract

The suppression of polymorphic major histocompatibility complex antigen expression in human trophoblasts is critical for the avoidance of a cell-mediated immune response by maternal lymphocytes against cells expressing paternal antigens. In this study, a repressor of major histocompatibility complex gene expression was cloned by negative immunoselection using a trophoblast cDNA expression library in interferon-γ-responsive human cells. The sequence of this regulatory gene was analyzed, and the functions of the transfected cDNA or microinjected gene product were examined in interferon-γ-responsive cells by immunocytochemical methods. The repressor, called TSU— trophoblast STAT (signal transducers and activators of transcription) utron (untranslated region of an mRNA)—reduced STAT1 nuclear translocation and suppressed major histocompatibility complex class II antigen expression at high doses of interferon-γ and class I expression at low doses of interferon-γ. TSU encoded a small, untranslated poly-A⁺-RNA that appeared to bind STAT1 through pairs of motifs analogous to STAT-binding promoter sequences. These promoter-like motifs, but no open reading frame, were conserved in a TSU-related gene in goats. Northern blot analysis demonstrated that TSU was expressed as a 0.5-kilobase (kb) RNA in placenta and as an ubiquitous 4.4-kb RNA. TSU expression may protect trophoblasts from immune attack and promote the survival of the placenta and fetus.