Transcriptional regulation of the MHC class Ib genes HLA-E, HLA-F, and HLA-G

The restricted tissue expression of the MHC class Ib molecules HLA-E, HLA-F, and HLA-G has suggested specialized functions and tight transcriptional control of their genes. Transactivation of classical MHC class I genes is mediated by two groups of juxtaposed cis-acting elements, which can be viewed as regulatory modules. The most upstream module consists of the enhancer A and ISRE, and mediates constitutive and cytokine induced expression, whereas the SXY module is important for the constitutive and CIITA-mediated transactivation of MHC class I genes. Nucleotide sequence divergence in these regulatory elements in the promoters of HLA-E, HLA-F, or HLA-G determines their differential responsiveness to NF-κB, IRF1, and CIITA-mediated induction. HLA-E is not inducible by NF-κB or IRF1, but is responsive to IFN-γ through an upstream STAT1 binding site. Furthermore, HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-κB through the κB1 site of enhancer A, is responsive to IFN-γ through the ISRE, and is inducible by CIITA. Both regulatory modules are divergent in HLA-G rendering this gene unresponsive to NF-κB, IRF1, and CIITA-mediated induction. This implies a unique regulation of HLA-G transcription amongst the MHC class Ib genes.